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Wang Z, Liu Z, Lv M, Luan Z, Li T, Hu J. Novel histone modifications and liver cancer: emerging frontiers in epigenetic regulation. Clin Epigenetics 2025; 17:30. [PMID: 39980025 PMCID: PMC11841274 DOI: 10.1186/s13148-025-01838-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/08/2025] [Indexed: 02/22/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and its onset and progression are closely associated with epigenetic modifications, particularly post-translational modifications of histones (HPTMs). In recent years, advances in mass spectrometry (MS) have revealed a series of novel HPTMs, including succinylation (Ksuc), citrullination (Kcit), butyrylation (Kbhb), lactylation (Kla), crotonylation (Kcr), and 2-hydroxyisobutyrylation (Khib). These modifications not only expand the histone code but also play significant roles in key carcinogenic processes such as tumor proliferation, metastasis, and metabolic reprogramming in HCC. This review provides the first comprehensive analysis of the impact of novel HPTMs on gene expression, cellular metabolism, immune evasion, and the tumor microenvironment. It specifically focuses on their roles in promoting tumor stem cell characteristics, epithelial-mesenchymal transition (EMT), and therapeutic resistance. Additionally, the review highlights the dynamic regulation of these modifications by specific enzymes, including "writers," "readers," and "erasers."
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Affiliation(s)
- Zhonghua Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China
| | - Ziwen Liu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China
| | - Mengxin Lv
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China
| | - Zhou Luan
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China
| | - Tao Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China
| | - Jinhua Hu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China.
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Su L, Bu J, Yu J, Jin M, Meng G, Zhu X. Comprehensive review and updated analysis of DNA methylation in hepatocellular carcinoma: From basic research to clinical application. Clin Transl Med 2024; 14:e70066. [PMID: 39462685 PMCID: PMC11513202 DOI: 10.1002/ctm2.70066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/30/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary malignant tumour, ranking second in global mortality rates and posing significant health threats. Epigenetic alterations, particularly DNA methylation, have emerged as pivotal factors associated with HCC diagnosis, therapy, prognosis and malignant progression. However, a comprehensive analysis of the DNA methylation mechanism driving HCC progression and its potential as a therapeutic biomarker remains lacking. This review attempts to comprehensively summarise various aspects of DNA methylation, such as its mechanism, detection methods and biomarkers aiding in HCC diagnosis, treatment and prognostic assessment of HCC. It also explores the role of DNA methylation in regulating HCC's malignant progression and sorafenib resistance, alongside elaborating the therapeutic effects of DNA methyltransferase inhibitors on HCC. A detailed examination of these aspects underscores the significant research on DNA methylation in tumour cells to elucidate malignant progression mechanisms, identify diagnostic markers and develop new tumour-specific inhibitors for HCC. KEY POINTS: A comprehensive summary of various aspects of DNA methylation, such as its mechanism, detection methods and biomarkers aiding in diagnosis and treatment. The role of DNA methylation in regulating hepatocellular carcinoma's (HCC) malignant progression and sorafenib resistance, alongside elaborating therapeutic effects of DNA methyltransferase inhibitors. Deep research on DNA methylation is critical for discovering novel tumour-specific inhibitors for HCC.
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Affiliation(s)
- Lin Su
- Department of Pain ManagementShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Jiawen Bu
- Department of Colorectal SurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Jiahui Yu
- Department of UltrasoundShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Mila Jin
- Department of Operation RoomThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Guanliang Meng
- Department of UrologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Xudong Zhu
- Department of OncologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
- Department of General SurgeryCancer Hospital of China Medical UniversityShenyangLiaoningChina
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Zhou X, Man M, Cui M, Zhou X, Hu Y, Liu Q, Deng Y. Relationship between EZH2 expression and prognosis of patients with hepatocellular carcinoma using a pathomics predictive model. Heliyon 2024; 10:e38562. [PMID: 39640777 PMCID: PMC11619983 DOI: 10.1016/j.heliyon.2024.e38562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 09/04/2024] [Accepted: 09/26/2024] [Indexed: 12/07/2024] Open
Abstract
Background Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is overexpressed in hepatocellular carcinoma, promoting tumorigenesis and correlating with poor prognosis. Traditional histopathological examinations are insufficient to accurately predict hepatocellular carcinoma (HCC) survival; however, pathomics models can predict EZH2 expression and HCC prognosis. This study aimed to investigate the relationship between pathomics features and EZH2 expression for predicting overall survival of patients with HCC. Methods We analyzed 267 patients with HCC from the Cancer Genome Atlas database, with available pathological images and gene expression data. RNA sequencing data were divided into high and low EZH2 expression groups for prognosis and survival analysis. Pathological image features were screened using mRMR_RFE. A pathological model was constructed using a gradient boosting machine (GBM) algorithm, and efficiency evaluation and survival analysis of the model were performed. The R package "survminer" took the pathomics score (PS) cutoff value of 0.4628 to divide the patients into two groups: high and low PS expression. Survival analyses included Kaplan-Meier curve analysis, univariate and multivariate Cox regression analyses, and interaction tests. Potential pathomechanisms were explored through enrichment, differential, immune cell infiltration abundance, and gene mutation analyses. Result EZH2 was highly expressed in tumor samples but poorly expressed in normal tissue samples. Univariate and multivariate Cox regression analyses revealed that EZH2 was an independent risk factor for HCC (hazard ratio [HR], 2.792 and 3.042, respectively). Seven imaging features were selected to construct a pathomics model to predict EZH2. Decision curve analysis showed that the model had high clinical utility. Multivariate Cox regression analysis showed that high PS expression was an independent risk factor for HCC prognosis (HR, 2.446). The Kaplan-Meier curve showed that high PS expression was a risk factor for overall survival. Conclusion EZH2 expression can affect the prognosis of patients with liver cancer. Our pathological model could predict EZH2 expression and prognosis of patients with HCC with high accuracy and robustness, making it a new and potentially valuable tool.
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Affiliation(s)
- Xulin Zhou
- Department of Oncology, Hefei BOE Hospital, Hefei, PR China
| | - Muran Man
- Department of Oncology, People's Hospital of Shizhong District, Zaozhuang City, Shandong Province, PR China
| | - Min Cui
- Affiliated Hospital Of Jining Medical University (Shanxian Central Hospital), Heze City, Shandong Province, PR China
| | - Xiang Zhou
- People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, Xinjiang, CN, PR China
| | - Yan Hu
- Department of Oncology, Hefei BOE Hospital, Hefei, PR China
| | - Qinghua Liu
- Department of Oncology, Deyang People's Hospital, Deyang, Sichuan, CN, PR China
| | - Youxing Deng
- Department of Oncology, Hefei BOE Hospital, Hefei, PR China
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Yang J, Zhang Z, Pang C, Cao D, Yan D, Fan J. Comprehensive analysis of CXCL10 and MIP-3a reveals their potential clinical application in hepatocellular carcinoma. Transl Oncol 2024; 48:102071. [PMID: 39098213 PMCID: PMC11359764 DOI: 10.1016/j.tranon.2024.102071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 07/02/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024] Open
Abstract
Chemokines play a crucial role in the pathogenesis of patients with hepatocellular carcinoma (HCC). The expression levels of interferon-γ-induced protein-10 (CXCL10) and macrophage inflammatory protein-3α (MIP-3a) were investigated to clarify their clinical significance in HCC. The protein levels of CXCL10 and MIP-3a in the serum of 105 HBV-associated HCC patients, 50 patients with liver cirrhosis (LC), 50 patients with chronic hepatitis B (CHB) and 50 healthy donors (HC) were detected by liquid chip technology (Luminex) or ELISA. In addition, their mRNA levels were also determined in liver cancer and adjacent cancer tissue (paracancer; ParaCa) from 65 HCC patients. The online database UALCAN was used to analyze the association between CXCL10 and pathological manifestations of liver cancer. In addition, the diagnostic value of CXCL10/MIP-3a and AFP in HCC patients was determined by analyzing the Receiver Operating Characteristic Curve (ROC). The protein concentrations of CXCL10 and MIP-3a were significantly higher in the HCC group than in the LC, CHB and HC groups. CXCL10 in sera and liver cancer tissues is significantly positively correlated with ALT, but no significance between CXCL10 in ParaCa tissues and sera-ALT. Their mRNA is significantly higher in cancer tissues than in ParaCa tissues. The areas under the ROC curve of CXCL10, MIP-3a, CXCL10 and MIP-3a combined and AFP were 0.9169, 0.9261, 0.9299 and 0.7880, respectively. Elevated chemokines CXCL10 and MIP-3a in HCC patients may be associated with the clinical manifestation of HCC and could be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.
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Affiliation(s)
- Jiezuan Yang
- The First Affiliated Hospital, Zhejiang University School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Hangzhou 310003, China.
| | - Zhengliang Zhang
- Department of Laboratory Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Caihong Pang
- Department of Transfusion, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Dan Cao
- The First Affiliated Hospital, Zhejiang University School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Hangzhou 310003, China
| | - Dong Yan
- The First Affiliated Hospital, Zhejiang University School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Hangzhou 310003, China.
| | - Jun Fan
- The First Affiliated Hospital, Zhejiang University School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Hangzhou 310003, China
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Zhao J, Liu Z, Yang K, Shen S, Peng J. DNA methylation regulator-based molecular subtyping and tumor microenvironment characterization in hepatocellular carcinoma. Front Immunol 2024; 15:1333923. [PMID: 38736884 PMCID: PMC11082416 DOI: 10.3389/fimmu.2024.1333923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Backgroud Although recent studies have reported the regulation of the immune response in hepatocellular carcinoma (HCC) through DNA methylation, the comprehensive impact methylation modifications on tumor microenvironment characteristics and immunotherapy efficacy has not been fully elucidated. Methods In this research, we conducted a comprehensive assessment of the patterns of DNA methylation regulators and the profiles of the tumor microenvironment (TME) in HCC, focusing on 21 specific DNA methylation regulators. We subsequently developed a unique scoring system, a DNA methylation score (DMscore), to assess the individual DNA methylation modifications among the three distinct methylation patterns for differentially expressed genes (DEGs). Results Three distinct methylation modification patterns were identified with distinct TME infiltration characteristics. We demonstrated that the DMscore could predict patient subtype, TME infiltration, and patient prognosis. A low DMscore, characterized by an elevated tumor mutation burden (TMB), hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, and immune activation, indicates an inflamed tumor microenvironment phenotype with a 5-year survival rate of 7.8%. Moreover, a low DMscore appeared to increase the efficacy of immunotherapy in the anti-CTLA-4/PD-1/PD-L1 cohort. Conclusions In brief, this research has enhanced our understanding of the correlation between modifications in DNA methylation patterns and the profile of the tumor microenvironment in individuals diagnosed with HCC. The DMscore may serve as an alternative biomarker for survival and efficacy of immunotherapy in patients with HCC.
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Affiliation(s)
- Junsheng Zhao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengtao Liu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Keda Yang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Sijia Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Baek M, Kim M, Choi HI, Binas B, Cha J, Jung KH, Choi S, Chai YG. Identification of differentially expressed mRNA/lncRNA modules in acutely regorafenib-treated sorafenib-resistant Huh7 hepatocellular carcinoma cells. PLoS One 2024; 19:e0301663. [PMID: 38603701 PMCID: PMC11008899 DOI: 10.1371/journal.pone.0301663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 03/20/2024] [Indexed: 04/13/2024] Open
Abstract
The multikinase inhibitor sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but many patients become sorafenib-resistant (SR). This study investigated the efficacy of another kinase inhibitor, regorafenib (Rego), as a second-line treatment. We produced SR HCC cells, wherein the PI3K-Akt, TNF, cAMP, and TGF-beta signaling pathways were affected. Acute Rego treatment of these cells reversed the expression of genes involved in TGF-beta signaling but further increased the expression of genes involved in PI3K-Akt signaling. Additionally, Rego reversed the expression of genes involved in nucleosome assembly and epigenetic gene expression. Weighted gene co-expression network analysis (WGCNA) revealed four differentially expressed long non-coding RNA (DElncRNA) modules that were associated with the effectiveness of Rego on SR cells. Eleven putative DElncRNAs with distinct expression patterns were identified. We associated each module with DEmRNAs of the same pattern, thus obtaining DElncRNA/DEmRNA co-expression modules. We discuss the potential significance of each module. These findings provide insights and resources for further investigation into the potential mechanisms underlying the response of SR HCC cells to Rego.
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Affiliation(s)
- Mina Baek
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Minjae Kim
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Hae In Choi
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Bert Binas
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Junho Cha
- Department of Applied Artificial Intelligence, Hanyang University, Ansan, Republic of Korea
| | - Kyoung Hwa Jung
- Department of Biopharmaceutical System, Gwangmyeong Convergence Technology Campus of Korea Polytechnic II, Incheon, Republic of Korea
| | - Sungkyoung Choi
- Department of Applied Artificial Intelligence, Hanyang University, Ansan, Republic of Korea
- Department of Mathematical Data Science, Hanyang University, Ansan, Republic of Korea
| | - Young Gyu Chai
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
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Cui JW, Li Y, Yang Y, Yang HK, Dong JM, Xiao ZH, He X, Guo JH, Wang RQ, Dai B, Zhou ZL. Tumor immunotherapy resistance: Revealing the mechanism of PD-1 / PD-L1-mediated tumor immune escape. Biomed Pharmacother 2024; 171:116203. [PMID: 38280330 DOI: 10.1016/j.biopha.2024.116203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/15/2024] [Accepted: 01/22/2024] [Indexed: 01/29/2024] Open
Abstract
Tumor immunotherapy, an innovative anti-cancer therapy, has showcased encouraging outcomes across diverse tumor types. Among these, the PD-1/PD-L1 signaling pathway is a well-known immunological checkpoint, which is significant in the regulation of immune evasion by tumors. Nevertheless, a considerable number of patients develop resistance to anti-PD-1/PD-L1 immunotherapy, rendering it ineffective in the long run. This research focuses on exploring the factors of PD-1/PD-L1-mediated resistance in tumor immunotherapy. Initially, the PD-1/PD-L1 pathway is characterized by its role in facilitating tumor immune evasion, emphasizing its role in autoimmune homeostasis. Next, the primary mechanisms of resistance to PD-1/PD-L1-based immunotherapy are analyzed, including tumor antigen deletion, T cell dysfunction, increased immunosuppressive cells, and alterations in the expression of PD-L1 within tumor cells. The possible ramifications of altered metabolism, microbiota, and DNA methylation on resistance is also described. Finally, possible resolution strategies for dealing with anti-PD-1/PD-L1 immunotherapy resistance are discussed, placing particular emphasis on personalized therapeutic approaches and the exploration of more potent immunotherapy regimens.
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Affiliation(s)
- Jia-Wen Cui
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Jinan University, Guangzhou, China
| | - Yao Li
- College of Pharmacy, Macau University of Science and Technology (MUST), China
| | - Yang Yang
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China
| | - Hai-Kui Yang
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jia-Mei Dong
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Zhi-Hua Xiao
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Jinan University, Guangzhou, China
| | - Xin He
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jia-Hao Guo
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Jinan University, Guangzhou, China
| | - Rui-Qi Wang
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China.
| | - Bo Dai
- Department of Cardiology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan City 528200, Guangdong Province, China.
| | - Zhi-Ling Zhou
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China.
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Ren X, Wang X, Zheng G, Wang S, Wang Q, Yuan M, Xu T, Xu J, Huang P, Ge M. Targeting one-carbon metabolism for cancer immunotherapy. Clin Transl Med 2024; 14:e1521. [PMID: 38279895 PMCID: PMC10819114 DOI: 10.1002/ctm2.1521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/15/2023] [Accepted: 12/10/2023] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND One-carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune-related adverse events in patients. METHODS We collected numerous literatures to explain the roles of one-carbon metabolism in cancer immunotherapy. RESULTS In this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future. CONCLUSION Targeting one-carbon metabolism is useful for cancer immunotherapy.
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Affiliation(s)
- Xinxin Ren
- Department of Head and Neck SurgeryOtolaryngology & Head and Neck Center, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhouZhejiangChina
- Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Malignant TumorHangzhouZhejiangChina
- Department of PathologyCancer CenterZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhouZhejiangChina
| | - Xiang Wang
- Department of PharmacyAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Guowan Zheng
- Department of Head and Neck SurgeryOtolaryngology & Head and Neck Center, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhouZhejiangChina
- Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Malignant TumorHangzhouZhejiangChina
| | - Shanshan Wang
- Department of PharmacyCenter for Clinical PharmacyCancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeHangzhouZhejiangChina
| | - Qiyue Wang
- Department of Head and Neck SurgeryOtolaryngology & Head and Neck Center, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhouZhejiangChina
- Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Malignant TumorHangzhouZhejiangChina
| | - Mengnan Yuan
- Department of PharmacyCenter for Clinical PharmacyCancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeHangzhouZhejiangChina
| | - Tong Xu
- Department of PharmacyCenter for Clinical PharmacyCancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeHangzhouZhejiangChina
| | - Jiajie Xu
- Department of Head and Neck SurgeryOtolaryngology & Head and Neck Center, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhouZhejiangChina
- Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Malignant TumorHangzhouZhejiangChina
| | - Ping Huang
- Department of PharmacyCenter for Clinical PharmacyCancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeHangzhouZhejiangChina
| | - Minghua Ge
- Department of Head and Neck SurgeryOtolaryngology & Head and Neck Center, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhouZhejiangChina
- Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Malignant TumorHangzhouZhejiangChina
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Lu S, Duan R, Cong L, Song Y. The effects of ARID1A mutation in gastric cancer and its significance for treatment. Cancer Cell Int 2023; 23:296. [PMID: 38008753 PMCID: PMC10676575 DOI: 10.1186/s12935-023-03154-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 11/21/2023] [Indexed: 11/28/2023] Open
Abstract
Gastric cancer (GC) has emerged as a significant issue in public health all worldwide as a result of its high mortality rate and dismal prognosis. AT-rich interactive domain 1 A (ARID1A) is a vital component of the switch/sucrose-non-fermentable (SWI/SNF) chromatin remodeling complex, and ARID1A mutations occur in various tumors, leading to protein loss and decreased expression; it then affects the tumor biological behavior or prognosis. More significantly, ARID1A mutations will likely be biological markers for immune checkpoint blockade (ICB) treatment and selective targeted therapy. To provide theoretical support for future research on the stratification of individuals with gastric cancer with ARID1A as a biomarker to achieve precision therapy, we have focused on the clinical significance, predictive value, underlying mechanisms, and possible treatment strategies for ARID1A mutations in gastric cancer in this review.
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Affiliation(s)
- Shan Lu
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Ruifeng Duan
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Liang Cong
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Ying Song
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China.
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10
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Yan M, Cao H, Tao K, Xiao B, Chu Y, Ma D, Huang X, Han Y, Ji T. HDACs alters negatively to the tumor immune microenvironment in gynecologic cancers. Gene 2023; 885:147704. [PMID: 37572797 DOI: 10.1016/j.gene.2023.147704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/14/2023]
Abstract
The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas and Human Protein Atlas to examine HDAC expression in breast, cervical, ovarian, and endometrial cancers. Elevated HDAC expression correlated with poor prognosis and highly malignant cancer subtypes. Gene Set Enrichment Analysis revealed positive associations between HDAC expression and tumor proliferation signature, while negative associations were found with tumor inflammation signature. Increased HDAC expression was linked to reduced infiltration of natural killer (NK), NKT, and CD8+ T cells, along with negative associations with the expression of PSMB10, NKG7, CCL5, CD27, HLA-DQA1, and HLA-DQB1. In a murine 4T1 breast cancer model, treatment with suberoylanilide hydroxamic acid (SAHA; HDAC inhibitor) and PD-1 antibody significantly inhibited tumor growth and infiltration of CD3+ and CD8+ T cells. Real-time polymerase chain reaction revealed upregulated expressions of Psmb10, Nkg7, Ccl5, Cd8a, Cxcr6, and Cxcl9 genes, while Ctnnb1 and Myc genes were inhibited, indicating tumor suppression and immune microenvironment activation. Our study revealed that HDACs play tumor-promoting and immunosuppressive roles in gynecologic cancers, suggesting HDAC inhibitors as potential therapeutic agents for these cancers.
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Affiliation(s)
- Miao Yan
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Cao
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kangjia Tao
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bing Xiao
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yifan Chu
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ding Ma
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyuan Huang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingyan Han
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Teng Ji
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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11
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Chai JW, Hu XW, Zhang MM, Dong YN. Seven chromatin regulators as immune cell infiltration characteristics, potential diagnostic biomarkers and drugs prediction in hepatocellular carcinoma. Sci Rep 2023; 13:18643. [PMID: 37903974 PMCID: PMC10616163 DOI: 10.1038/s41598-023-46107-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/27/2023] [Indexed: 11/01/2023] Open
Abstract
Treatment is challenging due to the heterogeneity of hepatocellular carcinoma (HCC). Chromatin regulators (CRs) are important in epigenetics and are closely associated with HCC. We obtained HCC-related expression data and relevant clinical data from The Cancer Genome Atlas (TCGA) databases. Then, we crossed the differentially expressed genes (DEGs), immune-related genes and CRs to obtain immune-related chromatin regulators differentially expressed genes (IRCR DEGs). Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to select the prognostic gene and construct a risk model for predicting prognosis in HCC, followed by a correlation analysis of risk scores with clinical characteristics. Finally, we also carried out immune microenvironment analysis and drug sensitivity analysis, the correlation between risk score and clinical characteristics was analyzed. In addition, we carried out immune microenvironment analysis and drug sensitivity analysis. Functional analysis suggested that IRCR DEGs was mainly enriched in chromatin-related biological processes. We identified and validated PPARGC1A, DUSP1, APOBEC3A, AIRE, HDAC11, HMGB2 and APOBEC3B as prognostic biomarkers for the risk model construction. The model was also related to immune cell infiltration, and the expression of CD48, CTLA4, HHLA2, TNFSF9 and TNFSF15 was higher in high-risk group. HCC patients in the high-risk group were more sensitive to Axitinib, Docetaxel, Erlotinib, and Metformin. In this study, we construct a prognostic model of immune-associated chromatin regulators, which provides new ideas and research directions for the accurate treatment of HCC.
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Affiliation(s)
- Jin-Wen Chai
- Department of Oncology, Laizhou Traditional Chinese Medicine Hospital, Laizhou, Shandong, China
| | - Xi-Wen Hu
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Miao-Miao Zhang
- Department of Oncology, Laizhou Traditional Chinese Medicine Hospital, Laizhou, Shandong, China
| | - Yu-Na Dong
- Department of Gastroenterology, Laizhou People's Hospital, No.1718 Wuli Street, Laizhou, Shandong, China.
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12
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Sukowati C, Cabral LKD, Anfuso B, Dituri F, Negro R, Giannelli G, Tiribelli C. PD-L1 Downregulation and DNA Methylation Inhibition for Molecular Therapy against Cancer Stem Cells in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:13357. [PMID: 37686163 PMCID: PMC10487900 DOI: 10.3390/ijms241713357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous cancer characterized by various cellular subtypes. This study investigates the potential of a combination strategy using immunotherapy and epigenetic reprogramming against HCC. We used a transgenic HCC mouse C57BL/6J-TG(ALB1HBV)44BRI/J to assess the dynamics of the programmed death receptor and its ligand (PD-1/PD-L1) and DNA methylation markers. In parallel, PD-L1 RNA silencing was performed in various human HCC cell lines, while combination therapy was performed in a co-culture system using long-term exposure of 5-Azacytidine (5-AZA) and an anti-PD-L1. Data from the mouse model showed that the expressions of Pdcd1, Pdcd1l1, and DNA methyltransferase 1 (Dnmt1) were significantly higher in HCC as compared to the wild-type mice (p < 0.01), supported by the high presence of PD-L1 methylated DNA. In HCC cell lines, PD-L1 silencing was accompanied by DNMT1 reduction, mostly noted in aggressive HCC cell lines, followed by the dysregulation of the cancer stem cell marker EpCAM. In combination therapy, the growth of HCC cells and lymphocytes was limited by the PD-L1 antibody, further reduced in the presence of 5-AZA by up to 20% (p < 0.001). The data demonstrated that combination therapy might be an option as a potential treatment for heterogeneous HCC.
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Affiliation(s)
- Caecilia Sukowati
- Liver Cancer Unit, Italian Liver Foundation NPO, AREA Science Park, Basovizza, 34049 Trieste, Italy (C.T.)
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia
| | - Loraine Kay D. Cabral
- Liver Cancer Unit, Italian Liver Foundation NPO, AREA Science Park, Basovizza, 34049 Trieste, Italy (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, Piazzale Europa, 1, 34127 Trieste, Italy
| | - Beatrice Anfuso
- Department of Life Sciences, University of Trieste, Piazzale Europa, 1, 34127 Trieste, Italy
| | - Francesco Dituri
- National Institute of Gastroenterology, IRCCS Saverio de Bellis Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
| | - Roberto Negro
- National Institute of Gastroenterology, IRCCS Saverio de Bellis Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
| | - Gianluigi Giannelli
- National Institute of Gastroenterology, IRCCS Saverio de Bellis Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
| | - Claudio Tiribelli
- Liver Cancer Unit, Italian Liver Foundation NPO, AREA Science Park, Basovizza, 34049 Trieste, Italy (C.T.)
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13
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Zimmerman SM, Lin PN, Souroullas GP. Non-canonical functions of EZH2 in cancer. Front Oncol 2023; 13:1233953. [PMID: 37664059 PMCID: PMC10473085 DOI: 10.3389/fonc.2023.1233953] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 07/21/2023] [Indexed: 09/05/2023] Open
Abstract
Mutations in chromatin modifying genes frequently occur in many kinds of cancer. Most mechanistic studies focus on their canonical functions, while therapeutic approaches target their enzymatic activity. Recent studies, however, demonstrate that non-canonical functions of chromatin modifiers may be equally important and therapeutically actionable in different types of cancer. One epigenetic regulator that demonstrates such a dual role in cancer is the histone methyltransferase EZH2. EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which plays a crucial role in cell identity, differentiation, proliferation, stemness and plasticity. While much of the regulatory functions and oncogenic activity of EZH2 have been attributed to its canonical, enzymatic activity of methylating lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark, recent studies suggest that non-canonical functions that are independent of H3K27me3 also contribute towards the oncogenic activity of EZH2. Contrary to PRC2's canonical repressive activity, mediated by H3K27me3, outside of the complex EZH2 can directly interact with transcription factors and oncogenes to activate gene expression. A more focused investigation into these non-canonical interactions of EZH2 and other epigenetic/chromatin regulators may uncover new and more effective therapeutic strategies. Here, we summarize major findings on the non-canonical functions of EZH2 and how they are related to different aspects of carcinogenesis.
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Affiliation(s)
- Sarah M. Zimmerman
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Phyo Nay Lin
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - George P. Souroullas
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Division of Oncology, Molecular Oncology Section, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Siteman Comprehensive Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
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14
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Salama BM, Helmy MW, Fouad H, Shamaa MM, Houssen ME. The Synergistic Antitumor Effect of Decitabine and Vorinostat Combination on HepG2 Human Hepatocellular Carcinoma Cell Line via Epigenetic Modulation of Autophagy-Apoptosis Molecular Crosstalk. Curr Issues Mol Biol 2023; 45:5935-5949. [PMID: 37504291 PMCID: PMC10378248 DOI: 10.3390/cimb45070375] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/09/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a worldwide health issue. Epigenetic alterations play a crucial role in HCC tumorigenesis. Using epigenetic modulators for HCC treatment confers a promising therapeutic effect. The aim of this study was to explore the effect of a decitabine (DAC) and vorinostat (VOR) combination on the crosstalk between apoptosis and autophagy in the HCC HepG2 cell line at 24 h and 72 h. Median inhibitory concentrations (IC50s) of VOR and DAC were assessed in the HepG2 cell line. The activity of caspase-3 was evaluated colorimetrically, and Cyclin D1(CCND1), Bcl-2, ATG5, ATG7, and P62 levels were assessed using ELISA at different time intervals (24 h and 72 h), while LC3IIB and Beclin-1gene expression were measured by using qRT-PCR. The synergistic effect of VOR and DAC was confirmed due to the observed combination indices (CIs) and dose reduction indices (DRIs). The combined treatment with both drugs inhibited the proliferation marker (CCND1), and enhanced apoptosis compared with each drug alone at 24 h and 72 h (via active caspase-3 upregulation and Bcl-2 downregulation). Moreover, the combination induced autophagy as an early event via upregulation of Beclin-1, LC3IIB, ATG5, and ATG7 gene expression. The initial induction of autophagy started to decrease after 72 h due to Beclin-1 downregulation, and there was decreased expression of LC3IIB compared with the value at 24 h. Herein, epigenetic modulation via the VOR/DAC combination showed an antitumor effect through the coordination of an autophagy-apoptosis crosstalk and promotion of autophagy-induced apoptosis, which ultimately led to the cellular death of HCC cancer cells.
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Affiliation(s)
- Basant M Salama
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt
| | - Maged W Helmy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt
- Pharmacology and Toxicology Department, Clinical and Biological Sciences Division, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria 1029, Egypt
| | - Hosny Fouad
- Pharmacology Department, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
- Department of Biochemistry, Clinical and Biological Science Division, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria 1029, Egypt
| | - Marium M Shamaa
- Department of Biochemistry, Clinical and Biological Science Division, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria 1029, Egypt
| | - Maha E Houssen
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt
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15
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Akce M, El-Rayes BF, Wajapeyee N. Combinatorial targeting of immune checkpoints and epigenetic regulators for hepatocellular carcinoma therapy. Oncogene 2023; 42:1051-1057. [PMID: 36854723 DOI: 10.1038/s41388-023-02646-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/16/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. The five-year survival rate of patients with unresectable HCC is about 12%. The liver tumor microenvironment (TME) is immune tolerant and heavily infiltrated with immunosuppressive cells. Immune checkpoint inhibitors (ICIs), in some cases, can reverse tumor cell immune evasion and enhance antitumor immunity. Rapidly evolving ICIs have expanded systemic treatment options in advanced HCC; however, single-agent ICIs achieve a limited 15-20% objective response rate in advanced HCC. Therefore, other combinatorial approaches that amplify the efficacy of ICIs or suppress other tumor-promoting pathways may enhance clinical outcomes. Epigenetic alterations (e.g., changes in chromatin states and non-genetic DNA modifications) have been shown to drive HCC tumor growth and progression as well as their response to ICIs. Recent studies have combined ICIs and epigenetic inhibitors in preclinical and clinical settings to contain several cancers, including HCC. In this review, we outline current ICI treatments for HCC, the mechanism behind their successes and failures, and how ICIs can be combined with distinct epigenetic inhibitors to increase the durability of ICIs and potentially treat "immune-cold" HCC.
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Affiliation(s)
- Mehmet Akce
- Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center of University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL, 35233, USA.
| | - Bassel F El-Rayes
- Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center of University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL, 35233, USA
| | - Narendra Wajapeyee
- Department of Biochemistry and Molecular Genetics, O'Neal Comprehensive Cancer Center of University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL, 35233, USA.
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16
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Tao S, Liang S, Zeng T, Yin D. Epigenetic modification-related mechanisms of hepatocellular carcinoma resistance to immune checkpoint inhibition. Front Immunol 2023; 13:1043667. [PMID: 36685594 PMCID: PMC9845774 DOI: 10.3389/fimmu.2022.1043667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/28/2022] [Indexed: 01/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) constitutes most primary liver cancers and is one of the most lethal and life-threatening malignancies globally. Unfortunately, a substantial proportion of HCC patients are identified at an advanced stage that is unavailable for curative surgery. Thus, palliative therapies represented by multi-tyrosine kinase inhibitors (TKIs) sorafenib remained the front-line treatment over the past decades. Recently, the application of immune checkpoint inhibitors (ICIs), especially targeting the PD-1/PD-L1/CTLA-4 axis, has achieved an inspiring clinical breakthrough for treating unresectable solid tumors. However, many HCC patients with poor responses lead to limited benefits in clinical applications, which has quickly drawn researchers' attention to the regulatory mechanisms of immune checkpoints in HCC immune evasion. Evasion of immune surveillance by cancer is attributed to intricate reprogramming modulation in the tumor microenvironment. Currently, more and more studies have found that epigenetic modifications, such as chromatin structure remodeling, DNA methylation, histone post-translational modifications, and non-coding RNA levels, may contribute significantly to remodeling the tumor microenvironment to avoid immune clearance, affecting the efficacy of immunotherapy for HCC. This review summarizes the rapidly emerging progress of epigenetic-related changes during HCC resistance to ICIs and discusses the mechanisms of underlying epigenetic therapies available for surmounting immune resistance. Finally, we summarize the clinical advances in combining epigenetic therapies with immunotherapy, aiming to promote the formation of immune combination therapy strategies.
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Affiliation(s)
- Shengwei Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Shuhang Liang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Taofei Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Dalong Yin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
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17
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dos Reis FD, Jerónimo C, Correia MP. Epigenetic modulation and prostate cancer: Paving the way for NK cell anti-tumor immunity. Front Immunol 2023; 14:1152572. [PMID: 37090711 PMCID: PMC10113550 DOI: 10.3389/fimmu.2023.1152572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/06/2023] [Indexed: 04/25/2023] Open
Abstract
Immunoepigenetics is a growing field, as there is mounting evidence on the key role played by epigenetic mechanisms in the regulation of tumor immune cell recognition and control of immune cell anti-tumor responses. Moreover, it is increasingly acknowledgeable a tie between epigenetic regulation and prostate cancer (PCa) development and progression. PCa is intrinsically a cold tumor, with scarce immune cell infiltration and low inflammatory tumor microenvironment. However, Natural Killer (NK) cells, main anti-tumor effector immune cells, have been frequently linked to improved PCa prognosis. The role that epigenetic-related mechanisms might have in regulating both NK cell recognition of PCa tumor cells and NK cell functions in PCa is still mainly unknown. Epigenetic modulating drugs have been showing boundless therapeutic potential as anti-tumor agents, however their role in immune cell regulation and recognition is scarce. In this review, we focused on studies addressing modulation of epigenetic mechanisms involved in NK cell-mediated responses, including both the epigenetic modulation of tumor cell NK ligand expression and NK cell receptor expression and function in different tumor models, highlighting studies in PCa. The integrated knowledge from diverse epigenetic modulation mechanisms promoting NK cell-mediated immunity in various tumor models might open doors for the development of novel epigenetic-based therapeutic options for PCa management.
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Affiliation(s)
- Filipa D. dos Reis
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal
- Master Program in Oncology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal
- Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Porto, Portugal
| | - Margareta P. Correia
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal
- Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Porto, Portugal
- *Correspondence: Margareta P. Correia,
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18
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Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, Wang C. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 20:203-222. [PMID: 36369487 DOI: 10.1038/s41575-022-00704-9] [Citation(s) in RCA: 304] [Impact Index Per Article: 101.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/13/2022] [Indexed: 11/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. A large proportion of patients with HCC are diagnosed at advanced stages and are only amenable to systemic therapies. We have witnessed the evolution of systemic therapies from single-agent targeted therapy (sorafenib and lenvatinib) to the combination of a checkpoint inhibitor plus targeted therapy (atezolizumab plus bevacizumab therapy). Despite remarkable advances, only a small subset of patients can obtain durable clinical benefit, and therefore substantial therapeutic challenges remain. In the past few years, emerging systemic therapies, including new molecular-targeted monotherapies (for example, donafenib), new immuno-oncology monotherapies (for example, durvalumab) and new combination therapies (for example, durvalumab plus tremelimumab), have shown encouraging results in clinical trials. In addition, many novel therapeutic approaches with the potential to offer improved treatment effects in patients with advanced HCC, such as sequential combination targeted therapy and next-generation adoptive cell therapy, have also been proposed and developed. In this Review, we summarize the latest clinical advances in the treatment of advanced HCC and discuss future perspectives that might inform the development of more effective therapeutics for advanced HCC.
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Affiliation(s)
- Chen Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hailin Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linmeng Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Boston, MA, USA. .,Jiahui International Cancer Center, Jiahui Health, Shanghai, China.
| | - René Bernards
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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19
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Nagaraju GP, Dariya B, Kasa P, Peela S, El-Rayes BF. Epigenetics in hepatocellular carcinoma. Semin Cancer Biol 2022; 86:622-632. [PMID: 34324953 DOI: 10.1016/j.semcancer.2021.07.017] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/17/2021] [Accepted: 07/25/2021] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and has a high fatality rate. Genetic and epigenetic aberrations are commonly observed in HCC. The epigenetic processes include chromatin remodelling, histone alterations, DNA methylation, and noncoding RNA (ncRNA) expression and are connected with the progression and metastasis of HCC. Due to their potential reversibility, these epigenetic alterations are widely targeted for the development of biomarkers. In-depth understanding of the epigenetics of HCC is critical for developing rational clinical strategies that can provide a meaningful improvement in overall survival and prediction of therapeutic outcomes. In this article, we have summarised the epigenetic modifications involved in HCC progression and highlighted the potential biomarkers for diagnosis and drug development.
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Affiliation(s)
- Ganji Purnachandra Nagaraju
- Department of Hematology & Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | - Begum Dariya
- Department of Biosciences and Biotechnology, Banasthali University, Banasthali, 304022, Rajasthan, India
| | - Prameswari Kasa
- Dr. L.V. Prasad Diagnostics and Research Laboratory, Khairtabad, Hyderabad 500004, India
| | - Sujatha Peela
- Department of Biotechnology, Dr. B.R. Ambedkar University, Srikakulam, 532410 AP, India
| | - Bassel F El-Rayes
- Department of Hematology & Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
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20
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Huang R, Wu Y, Zou Z. Combining EZH2 inhibitors with other therapies for solid tumors: more choices for better effects. Epigenomics 2022; 14:1449-1464. [PMID: 36601794 DOI: 10.2217/epi-2022-0320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
EZH2 is an epigenetic regulator that methylates lysine 27 on histone H3 (H3K27) and is closely related to the development and metastasis of tumors. It often shows gain-of-function mutations in hematological tumors, while it is often overexpressed in solid tumors. EZH2 inhibitors have shown good efficacy in hematological tumors in clinical trials but poor efficacy in solid tumors. Therefore, current research on EZH2 inhibitors has focused on exploring additional combination strategies in solid tumors. Herein we summarize the combinations and mechanisms of EZH2 inhibitors and other therapies, including immunotherapy, targeted therapy, chemotherapy, radiotherapy, hormone therapy and epigenetic therapy, both in clinical trials and preclinical studies, aiming to provide a reference for better antitumor effects.
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Affiliation(s)
- Rong Huang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Yirong Wu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Zhengyun Zou
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
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Harkus U, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data. Semin Cancer Biol 2022; 86:799-815. [PMID: 35065242 DOI: 10.1016/j.semcancer.2022.01.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths in the world, and for patients with advanced disease there are few therapeutic options available. The complex immunological microenvironment of HCC and the success of immunotherapy in several types of tumours, has raised the prospect of potential benefit for immune based therapies, such as immune checkpoint inhibitors (ICIs), in HCC. This has led to significant breakthrough research, numerous clinical trials and the rapid approval of multiple systemic drugs for HCC by regulatory bodies worldwide. Although some patients responded well to ICIs, many have failed to achieve significant benefit, while others showed unexpected and paradoxical deterioration. The aim of this review is to discuss the pathophysiology of HCC, the tumour microenvironment, key clinical trials evaluating ICIs in HCC, various resistance mechanisms to ICIs, and possible ways to overcome these impediments to improve patient outcomes.
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Affiliation(s)
- Uasim Harkus
- Townsville University Hospital, Townsville, Queensland 4811, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Pranavan Palamuthusingam
- College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; Townsville University Hospital, Townsville, Queensland 4811, Australia; Mater Hospital, Townsville, Queensland 4811, Australia
| | - Craig McFarlane
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales 2145, Australia.
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22
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Zhang L, Li HT, Shereda R, Lu Q, Weisenberger DJ, O'Connell C, Machida K, An W, Lenz HJ, El-Khoueiry A, Jones PA, Liu M, Liang G. DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma. Cancer Lett 2022; 548:215899. [PMID: 36087682 PMCID: PMC9563073 DOI: 10.1016/j.canlet.2022.215899] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/16/2022] [Accepted: 08/26/2022] [Indexed: 11/29/2022]
Abstract
The development of more effective targeted therapies for hepatocellular carcinoma (HCC) patients due to its aggressiveness is urgently needed. DNA methyltransferase inhibitors (DNMTis) represented the first clinical breakthrough to target aberrant cancer epigenomes. However, their clinical efficacies are still limited, in part due to an "epigenetic switch" in which a large group of genes that are demethylated by DNMTi treatment remain silenced by polycomb repressive complex 2 (PRC2) occupancy. EZH2 is the member of PRC2 that catalyzes the placement of H3K27me3 marks. EZH2 overexpression is correlated with poor HCC patient survival. We tested the combination of a DNMTi (5-aza-2'-deoxycytidine, DAC) and the EZH2 inhibitor (EZH2i) GSK126 in human HCC cell lines on drug sensitivity, DNA methylation, nucleosome accessibility, and gene expression profiles. Compared with single agent treatments, all HCC cell lines studied showed increased sensitivity after receiving both drugs concomitant with prolonged anti-proliferative changes and sustained reactivation of nascently-silenced genes. The increased number of up-regulated genes after combination treatment correlated with prolonged anti-proliferation effects and increased nucleosome accessibility. Combination treatments also activate demethylated promoters that are repressed by PRC2 occupancy. Furthermore, 13-31% of genes down-regulated by DNA methylation in primary HCC tumors were reactivated through this combination treatment scheme in vitro. Finally, the combination treatment also exacerbates anti-tumor immune responses, while most of these genes were downregulated in over 50% of primary HCC tumors. We have linked the anti-tumor effects of DAC and GSK126 combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for treatment efficacy for HCC patients.
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Affiliation(s)
- Lian Zhang
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA; Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hong-Tao Li
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA
| | - Rachel Shereda
- Van Andel Research Institute, Grand Rapids, MI, 49503, USA
| | - Qianjin Lu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daniel J Weisenberger
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Casey O'Connell
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA
| | - Keigo Machida
- Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA
| | - Woojin An
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Heinz-Josef Lenz
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA
| | - Anthony El-Khoueiry
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA
| | - Peter A Jones
- Van Andel Research Institute, Grand Rapids, MI, 49503, USA
| | - Minmin Liu
- Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
| | - Gangning Liang
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
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23
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Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials. Signal Transduct Target Ther 2022; 7:353. [PMID: 36198685 PMCID: PMC9535022 DOI: 10.1038/s41392-022-01200-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/03/2022] [Accepted: 09/18/2022] [Indexed: 11/08/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related death across the world. Unlike lung adenocarcinoma, patients with lung squamous cell carcinoma (LSCC) have not benefitted from targeted therapies. Although immunotherapy has significantly improved cancer patients' outcomes, the relatively low response rate and severe adverse events hinder the clinical application of this promising treatment in LSCC. Therefore, it is of vital importance to have a better understanding of the mechanisms underlying the pathogenesis of LSCC as well as the inner connection among different signaling pathways, which will surely provide opportunities for more effective therapeutic interventions for LSCC. In this review, new insights were given about classical signaling pathways which have been proved in other cancer types but not in LSCC, including PI3K signaling pathway, VEGF/VEGFR signaling, and CDK4/6 pathway. Other signaling pathways which may have therapeutic potentials in LSCC were also discussed, including the FGFR1 pathway, EGFR pathway, and KEAP1/NRF2 pathway. Next, chromosome 3q, which harbors two key squamous differentiation markers SOX2 and TP63 is discussed as well as its related potential therapeutic targets. We also provided some progress of LSCC in epigenetic therapies and immune checkpoints blockade (ICB) therapies. Subsequently, we outlined some combination strategies of ICB therapies and other targeted therapies. Finally, prospects and challenges were given related to the exploration and application of novel therapeutic strategies for LSCC.
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24
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Liu HH, Wang J, Zhang Y, Fan YC, Wang K. Prognostic potential of the small GTPase Ran and its methylation in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2022; 21:248-256. [PMID: 35367146 DOI: 10.1016/j.hbpd.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/03/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. The prognostic significance of Ran, a member of Ras superfamily, remains unclear in HCC patients. METHODS Based on The Cancer Genome Atlas (TCGA) database and Tumor Immune Estimation Resource (TIMER), we analyzed the correlations among Ran expression, promoter methylation and immune cell infiltration. We also investigated the Ran expression levels in HCC tissues and normal tissues by using quantitative real-time PCR. RESULTS Ran mRNA expression was significantly increased in HCC tissues compared with the normal tissues (P < 0.001). Time-dependent receiver operating characteristic (ROC) curves showed that Ran expression had predictive value of the 1-, 3- and 5-year overall survival for HCC patients, and the areas under the curves (AUC) were 0.747, 0.634 and 0.704, respectively. Cox regression analysis showed that Ran expression was an independent prognostic factor for HCC patients (HR = 1.492, 95% CI: 1.129-1.971, P = 0.005). We also found a negative relationship between Ran mRNA expression and its promoter methylation (r = -0.36, P < 0.001). High Ran expression and promoter hypomethylation predicted worse overall survival and progression-free survival (P < 0.05) and were involved in the progression of HCC. Ran expression exhibited significant correlations with immune infiltrates and prognostic immune-related genes. CONCLUSIONS The present study provides further insight into the prognosis of HCC, and Ran could serve as a biomarker for predicting the survival of HCC patients.
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Affiliation(s)
- Hui-Hui Liu
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250000, China
| | - Ju Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250000, China
| | - Ying Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250000, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250000, China; Shenzhen Research Institute of Shandong University, Shenzhen 518000, China; Institute of Hepatology, Shandong University, Jinan 250000, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250000, China; Shenzhen Research Institute of Shandong University, Shenzhen 518000, China; Institute of Hepatology, Shandong University, Jinan 250000, China.
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25
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Zhao Q, Wang Y, Zhao B, Chen H, Cai Z, Zheng Y, Zeng Y, Zhang D, Liu X. Neoantigen Immunotherapeutic-Gel Combined with TIM-3 Blockade Effectively Restrains Orthotopic Hepatocellular Carcinoma Progression. NANO LETTERS 2022; 22:2048-2058. [PMID: 35133159 DOI: 10.1021/acs.nanolett.1c04977] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Herein, we integrate the Hepa1-6 liver cancer-specific neoantigen, toll-like receptor 9 agonist and stimulator of interferon genes agonist by silk-hydrogel package, and combine with TIM-3 blockade to elicit robust antitumor immunity for effectively suppressing orthotopic hepatocellular carcinoma (HCC) progression. Unlike intradermal injection of simple mixed components with short-term immune protection, the neoantigen immunotherapeutic-gels evoke long-term immune protection to achieve significant prophylactic and therapeutic activity against HCC through only one-shot administration without any side effects. Notably, the synergized immunotherapy by further combining NGC-gels with TIM-3 antibody significantly reduces regulatory T-cells and increases the IFN-γ and IL-12p70 levels in tumor tissues for promoting the infiltration of IFN-γ+CD8+T-cells and 41BB+CD8+T-cells to achieve complete remission (4/7) and prevent pulmonary metastasis in orthotopic HCC, and establish long-term memory against tumor rechallenge with remarkably longer survival time (180 days). Overall, this study provides an attractive and promising synergistic strategy for HCC immunotherapy with possible clinical translation prospects.
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Affiliation(s)
- Qingfu Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
| | - Yunhao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
| | - Binyu Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
| | - Hengkai Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
| | - Zhixiong Cai
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, P. R. China
| | - Youshi Zheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, P. R. China
| | - Yongyi Zeng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Da Zhang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, P. R. China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- CAS Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, P. R. China
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26
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The Relevance of SOCS1 Methylation and Epigenetic Therapy in Diverse Cell Populations of Hepatocellular Carcinoma. Diagnostics (Basel) 2021; 11:diagnostics11101825. [PMID: 34679523 PMCID: PMC8534387 DOI: 10.3390/diagnostics11101825] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 12/11/2022] Open
Abstract
The suppressor of cytokine signaling 1 (SOCS1) is a tumor suppressor gene found to be hypermethylated in cancers. It is involved in the oncogenic transformation of cirrhotic liver tissues. Here, we investigated the clinical relevance of SOCS1 methylation and modulation upon epigenetic therapy in diverse cellular populations of hepatocellular carcinoma (HCC). HCC clinical specimens were evaluated for SOCS1 methylation and mRNA expression. The effect of 5-Azacytidine (5-AZA), a demethylation agent, was assessed in different subtypes of HCC cells. We demonstrated that the presence of SOCS1 methylation was significantly higher in HCC compared to peri-HCC and non-tumoral tissues (52% vs. 13% vs. 14%, respectively, p < 0.001). In vitro treatment with a non-toxic concentration of 5-AZA significantly reduced DNMT1 protein expression for stromal subtype lines (83%, 73%, and 79%, for HLE, HLF, and JHH6, respectively, p < 0.01) compared to cancer stem cell (CSC) lines (17% and 10%, for HepG2 and Huh7, respectively), with the strongest reduction in non-tumoral IHH cells (93%, p < 0.001). 5-AZA modulated the SOCS1 expression in different extents among the cells. It was restored in CSC HCC HepG2 and Huh7 more efficiently than sorafenib. This study indicated the relevance of SOCS1 methylation in HCC and how cellular heterogeneity influences the response to epigenetic therapy.
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Cheu JWS, Wong CCL. Mechanistic Rationales Guiding Combination Hepatocellular Carcinoma Therapies Involving Immune Checkpoint Inhibitors. Hepatology 2021; 74:2264-2276. [PMID: 33811765 DOI: 10.1002/hep.31840] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/08/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers because of late symptom manifestation leading to delayed diagnosis, which limits patients with HCC in terms of receiving curative surgical treatment. There are only a few therapeutic options for patients with advanced HCC. The emergence of immune checkpoint inhibitors (ICIs) brings HCC treatment to a stage at which nivolumab, an anti-programmed cell death protein 1 monoclonal antibody, achieves a 20% response rate. However, the large proportion of unresponsive patients drives the exploration of therapeutic strategies to improve ICIs' efficacy. Recent preclinical and clinical studies have suggested that ICIs, when used in combinations or when used with other cancer therapies, might elicit synergistic antitumor effects. However, the mechanistic rationales guiding different drug combinations to maximize this synergy remain largely ambiguous. In this review, we discuss different drug combinations used in HCC and the underlying mechanistic rationales, aiming to enhance the understanding of how these treatments can achieve synergy. This knowledge sets the foundation for the development of more effective and promising combination therapies for HCC.
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Affiliation(s)
| | - Carmen Chak-Lui Wong
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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Sanceau J, Gougelet A. Epigenetic mechanisms of liver tumor resistance to immunotherapy. World J Hepatol 2021; 13:979-1002. [PMID: 34630870 PMCID: PMC8473495 DOI: 10.4254/wjh.v13.i9.979] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/04/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor, which stands fourth in rank of cancer-related deaths worldwide. The incidence of HCC is constantly increasing in correlation with the epidemic in diabetes and obesity, arguing for an urgent need for new treatments for this lethal cancer refractory to conventional treatments. HCC is the paradigm of inflammation-associated cancer, since more than 80% of HCC emerge consecutively to cirrhosis associated with a vast remodeling of liver microenvironment. In the recent decade, immunomodulatory drugs have been developed and have given impressive results in melanoma and later in several other cancers. In the present review, we will discuss the recent advancements concerning the use of immunotherapies in HCC, in particular those targeting immune checkpoints, used alone or in combination with other anti-cancers agents. We will address why these drugs demonstrate unsatisfactory results in a high proportion of liver cancers and the mechanisms of resistance developed by HCC to evade immune response with a focus on the epigenetic-related mechanisms.
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Affiliation(s)
- Julie Sanceau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris 75006, France
| | - Angélique Gougelet
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris 75006, France
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29
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Bévant K, Desoteux M, Abdel Wahab AHA, Abdel Wahab SA, Metwally AM, Coulouarn C. DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer. Cells 2021; 10:2207. [PMID: 34571856 PMCID: PMC8468746 DOI: 10.3390/cells10092207] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/17/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways.
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Affiliation(s)
- Kevin Bévant
- Centre de Lutte Contre le Cancer Eugène Marquis, Inserm, University of Rennes 1, UMR_S 1242, COSS (Chemistry, Oncogenesis Stress Signaling), 35042 Rennes, France; (K.B.); (M.D.)
| | - Matthis Desoteux
- Centre de Lutte Contre le Cancer Eugène Marquis, Inserm, University of Rennes 1, UMR_S 1242, COSS (Chemistry, Oncogenesis Stress Signaling), 35042 Rennes, France; (K.B.); (M.D.)
| | | | - Sabrin A. Abdel Wahab
- Medical Laboratory Department, Students Hospital, Cairo University, Cairo 11796, Egypt;
| | - Ayman Mohamed Metwally
- Medical Laboratory Technology Department, College of Applied Health Science Technology, Misr University for Science and Technology (MUST), Al-Motamayez District, 6th of October P.O. Box 77, Egypt
| | - Cédric Coulouarn
- Centre de Lutte Contre le Cancer Eugène Marquis, Inserm, University of Rennes 1, UMR_S 1242, COSS (Chemistry, Oncogenesis Stress Signaling), 35042 Rennes, France; (K.B.); (M.D.)
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Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13164237. [PMID: 34439391 PMCID: PMC8392268 DOI: 10.3390/cancers13164237] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/15/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma is a life-threatening disease. Despite many efforts to understand the exact pathogenesis and the signaling pathways involved in its formation, treatment remains unsatisfactory. Currently, an important function in the development of neoplastic diseases and treatment effects is attributed to changes taking place at the epigenetic level. Epigenetic studies revealed modified methylation patterns in HCC, dysfunction of enzymes engaged in the DNA methylation process, the aberrant function of non-coding RNAs, and a set of histone modifications that influence gene expression. The aim of this review is to summarize the current knowledge on the role of epigenetics in the formation of hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy.
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Jiao J, Sanchez JI, Thompson EJ, Mao X, McCormick JB, Fisher-Hoch SP, Futreal PA, Zhang J, Beretta L. Somatic Mutations in Circulating Cell-Free DNA and Risk for Hepatocellular Carcinoma in Hispanics. Int J Mol Sci 2021; 22:ijms22147411. [PMID: 34299031 PMCID: PMC8304329 DOI: 10.3390/ijms22147411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 02/03/2023] Open
Abstract
Hispanics are disproportionally affected by liver fibrosis and hepatocellular carcinoma (HCC). Advanced liver fibrosis is a major risk factor for HCC development. We aimed at identifying somatic mutations in plasma cell-free DNA (cfDNA) of Hispanics with HCC and Hispanics with advanced liver fibrosis but no HCC. Targeted sequencing of over 262 cancer-associated genes identified nonsynonymous mutations in 22 of the 27 HCC patients. Mutations were detected in known HCC-associated genes (e.g., CTNNB1, TP53, NFE2L2, and ARID1A). No difference in cfDNA concentrations was observed between patients with mutations and those without detectable mutations. HCC patients with higher cfDNA concentrations or higher number of mutations had a shorter overall survival (p < 0.001 and p = 0.045). Nonsynonymous mutations were also identified in 17 of the 51 subjects with advanced liver fibrosis. KMT2C was the most commonly mutated gene. Nine genes were mutated in both subjects with advanced fibrosis and HCC patients. Again, no significant difference in cfDNA concentrations was observed between subjects with mutations and those without detectable mutations. Furthermore, higher cfDNA concentrations and higher number of mutations correlated with a death outcome in subjects with advanced fibrosis. In conclusion, cfDNA features are promising non-invasive markers for HCC risk prediction and overall survival.
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (J.J.); (J.I.S.)
| | - Jessica I. Sanchez
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (J.J.); (J.I.S.)
| | - Erika J. Thompson
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Xizeng Mao
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (X.M.); (P.A.F.); (J.Z.)
| | - Joseph B. McCormick
- Brownsville Regional Campus, School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX 78520, USA; (J.B.M.); (S.P.F.-H.)
| | - Susan P. Fisher-Hoch
- Brownsville Regional Campus, School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX 78520, USA; (J.B.M.); (S.P.F.-H.)
| | - P. Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (X.M.); (P.A.F.); (J.Z.)
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (X.M.); (P.A.F.); (J.Z.)
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (J.J.); (J.I.S.)
- Correspondence: ; Tel.: +1-713-792-9100
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Singh P, Kairuz D, Arbuthnot P, Bloom K. Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach. World J Gastroenterol 2021; 27:3182-3207. [PMID: 34163105 PMCID: PMC8218364 DOI: 10.3748/wjg.v27.i23.3182] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/23/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Global prophylactic vaccination programmes have helped to curb new hepatitis B virus (HBV) infections. However, it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma. As such, HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed. Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA (cccDNA) which establishes itself as a minichromosome in the nucleus of hepatocytes. As the viral transcription intermediate, the cccDNA is responsible for producing new virions and perpetuating infection. HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications. Two HBV proteins, X (HBx) and core (HBc) promote viral replication by modulating the cccDNA epigenome and regulating host cell responses. This includes viral and host gene expression, chromatin remodeling, DNA methylation, the antiviral immune response, apoptosis, and ubiquitination. Elimination of the cccDNA minichromosome would result in a sterilizing cure; however, this may be difficult to achieve. Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure. This review explores the cccDNA epigenome, how host and viral factors influence transcription, and the recent epigenetic therapies and epigenome engineering approaches that have been described.
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Affiliation(s)
- Prashika Singh
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Dylan Kairuz
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Kristie Bloom
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
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CXCL2/10/12/14 are prognostic biomarkers and correlated with immune infiltration in hepatocellular carcinoma. Biosci Rep 2021; 41:228875. [PMID: 34085699 PMCID: PMC8217985 DOI: 10.1042/bsr20204312] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 05/16/2021] [Accepted: 06/02/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND C-x-C motif chemokine ligands (CXCLs) are critical regulators of cancer immunity and angiogenesis, which affect disease progression and treatment responses. The character of each CXCL in the prognosis and immune infiltration of hepatocellular carcinoma (HCC) patients is unclear yet. METHODS Differentially expressed CXCLs between HCC and normal control were screened by Oncomine and GEPIA2. Genetic alternations of CXCLs in HCC were analyzed by cBioPortal. Clinicopathological relevance of CXCLs in HCC patients was analyzed using UALCAN. The prognostic value of CXCLs was evaluated using univariate and multivariate analyses. Correlations of CXCLs' expression with immune infiltration, chemokines and their receptors were assessed integrating TIMER, TISIDB, and GEPIA2. The co-expressed genes of CXCLs were discovered, and functional enrichment analysis was performed for them. RESULTS CXCL9/10 was significantly higher expressed while CXCL2/12/14 was lower expressed in HCC than normal tissues, but they didn't show significant clinicopathological relevance in HCC patients. High-expression of CXCL2/10/12/14 indicated favorable outcomes of HCC patients. The expression of CXCL9/10/12/14 was significantly positively correlated with not only the infiltration and biomarkers' expression of various tumor-infiltrating immune cells but also the abundance of chemokines and their receptors. The co-expressed genes of the five CXCLs were extracellular components and regulated immune or inflammatory responses and signaling pathways of chemokine, Toll-like receptor and tumor necrosis factor might be involved. CONCLUSION The present study proposed CXCL2/10/12/14 might predict outcomes of HCC patients and were extensively related with the immune microenvironment in HCC. It would be a prospective therapeutic strategy for HCC to enhance effective immunity surveillance through intervening in these CXCLs.
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Abstract
Improving the survival of patients with osteosarcoma has long proved challenging, although the treatment of this disease is on the precipice of advancement. The increasing feasibility of molecular profiling together with the creation of both robust model systems and large, well-annotated tissue banks has led to an increased understanding of osteosarcoma biology. The historical invariability of survival outcomes and the limited number of agents known to be active in the treatment of this disease facilitate clinical trials designed to identify efficacious novel therapies using small cohorts of patients. In addition, trial designs will increasingly consider the genetic background of the tumour through biomarker-based patient selection, thereby enriching for clinical activity. Indeed, osteosarcoma cells are known to express a number of surface proteins that might be of therapeutic relevance, including B7-H3, GD2 and HER2, which can be targeted using antibody-drug conjugates and/or adoptive cell therapies. In addition, immune-checkpoint inhibition might augment the latter approach by helping to overcome the immunosuppressive tumour microenvironment. In this Review, we provide a brief overview of current osteosarcoma therapy before focusing on the biological insights from the molecular profiling and preclinical modelling studies that have opened new therapeutic opportunities in this disease.
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Affiliation(s)
- Jonathan Gill
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Richard Gorlick
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Liu ZL, Liu JH, Staiculescu D, Chen J. Combination of molecularly targeted therapies and immune checkpoint inhibitors in the new era of unresectable hepatocellular carcinoma treatment. Ther Adv Med Oncol 2021; 13:17588359211018026. [PMID: 34104226 PMCID: PMC8150670 DOI: 10.1177/17588359211018026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.
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Affiliation(s)
- Ze-Long Liu
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jing-Hua Liu
- Department of Hepatobiliary Surgery and Professor Cai’s Laboratory, Linyi People’s Hospital, Linyi, Shandong Province, China
| | - Daniel Staiculescu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, No. 3, East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
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George A, Sahin I, Carneiro BA, Dizon DS, Safran HP, El-Deiry WS. Strategies to sensitize cancer cells to immunotherapy. Hum Vaccin Immunother 2021; 17:2595-2601. [PMID: 34019474 PMCID: PMC8475577 DOI: 10.1080/21645515.2021.1891817] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Recent years have seen the emergence of immunotherapy as a promising modality for treating a variety of cancers. However, the initial data have led to the ultimate reality that such a treatment does not work effectively in all cancers, nor does it universally result in long-lasting benefits, which can be partly attributed to the development of drug resistance- itself a major challenge. Worse, in some cases, immunotherapy can lead to accelerated tumor growth known as hyperprogression. Tumor sensitization is being pursued as a means to circumvent resistance to immunotherapy, and perhaps as a means to prevent hyperprogression. Such approaches aim to counteract features of immune resistance demonstrated by refractory tumors, paving the way for improved treatment effectiveness when standard immunotherapies such as immune checkpoint inhibitors are utilized. Sensitizing agents can be categorized by whether their target is a tumor-intrinsic or a tumor cell-extrinsic factor. Tumor-intrinsic sensitization strategies act directly on cancer cells, suppressing their anti-immune tendencies, whereas tumor cell-extrinsic sensitization strategies target the tumor microenvironment to more effectively mediate the desired therapeutic effects of immunotherapy.
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Affiliation(s)
- Andrew George
- Department of Chemistry, Brown University, Providence, RI, USA.,Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI, USA
| | - Ilyas Sahin
- Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA.,Division of Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Benedito A Carneiro
- Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA.,Division of Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA.,The Warren Alpert Medical School, Cancer Center at Brown University, Brown University, Providence, RI, USA
| | - Don S Dizon
- Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA.,Division of Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA.,The Warren Alpert Medical School, Cancer Center at Brown University, Brown University, Providence, RI, USA
| | - Howard P Safran
- Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA.,Division of Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA.,The Warren Alpert Medical School, Cancer Center at Brown University, Brown University, Providence, RI, USA
| | - Wafik S El-Deiry
- Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA.,Division of Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA.,The Warren Alpert Medical School, Cancer Center at Brown University, Brown University, Providence, RI, USA.,Department of Pathology & Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
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Zhang Y, Zhang H, Wu S. LncRNA-CCDC144NL-AS1 Promotes the Development of Hepatocellular Carcinoma by Inducing WDR5 Expression via Sponging miR-940. J Hepatocell Carcinoma 2021; 8:333-348. [PMID: 33977095 PMCID: PMC8104990 DOI: 10.2147/jhc.s306484] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/13/2021] [Indexed: 12/19/2022] Open
Abstract
Purpose This work was initiated to offer solid evidence regarding the expression and roles of long noncoding RNA (lncRNA) CCDC144NL-AS1 in hepatocellular carcinoma (HCC). Patients and Methods Cell Counting Kit-8 assay, flow cytometric analysis, and invasion assays were used to explore the malignant biological characteristics of cells. Immunohistochemistry (IHC), Western blotting analysis, and real-time quantitative PCR (RT-qPCR) were used to analyze the expression level of related proteins and nucleic acids. Bl6/Rag2/GammaC double knockout mice were used for HCC modeling to address the therapeutic value of CCDC144NL-AS1. Results CCDC144NL-AS1 was significantly upregulated in HCC tissue and had a marked relationship with the 5-year prognosis. In vitro study revealed that CCDC144NL-AS1 was highly expressed in HCC cell line MHCC97H but lowly expressed in normal hepatic cell line L02. Overexpression of CCDC144NL-AS1 in L02 enhanced the invasion and proliferation abilities of cells but inhibited the apoptosis rate. Knockdown of CCDC144NL-AS1 in MHCC97H weakened the invasion and proliferation abilities of cells but increased the apoptosis rate. CCDC144NL-AS1 was found to sponge miR-940 to induce the expression of WD repeat domain 5 (WDR5). ChIP-seq analysis identified that matrix metalloproteinase (MMP) 2, MMP9, and cyclin-dependent kinase (CDK) 1, CDK2, and CDK4 were all targets of WDR5. The recruitment of WDR5 to the promoter of these target genes upregulated the histone H3 lysine 4 trimethylation (H3K4me3) level in these regions and further induced the transcription of MMP2, MMP9, CDK1, CDK2, and CDK4. In vivo study revealed that compared to the normal liver tissue, CCDC144NL-AS1, WDR5, MMP2, MMP9, CDK1, CDK2, and CDK4 were all significantly upregulated in HCC tissue from the same mouse, while miR-940 was decreased. Besides, knockdown of CCDC144NL-AS1 or WDR5 or overexpression of miR-940 could all inhibit tumor growth. Conclusion CCDC144NL-AS1 drives HCC development by inducing MMP2/MMP9 and CDK1/CDK2/CDK4 expressions through miR-940/WDR5-regulated epigenetic pathway.
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Affiliation(s)
- Yingying Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Hongyu Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Shuhuan Wu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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Kim SH, Kang BC, Seong D, Lee WH, An JH, Je HU, Cha HJ, Chang HW, Kim SY, Kim SW, Han MW. EPHA3 Contributes to Epigenetic Suppression of PTEN in Radioresistant Head and Neck Cancer. Biomolecules 2021; 11:biom11040599. [PMID: 33919657 PMCID: PMC8073943 DOI: 10.3390/biom11040599] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/12/2021] [Accepted: 04/16/2021] [Indexed: 11/16/2022] Open
Abstract
EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro and in vivo. In this study, we investigated the mechanisms of PTEN regulation through EPHA3-related signaling. Increased DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2) levels, along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, correlated with decreased levels of PTEN in radioresistant head and neck cancer cells. Furthermore, PTEN is regulated in two ways: DNMT1-mediated DNA methylation, and EZH2-mediated histone methylation through EPHA3/C-myc signaling. Our results suggest that EPHA3 could display a novel regulatory mechanism for the epigenetic regulation of PTEN in radioresistant head and neck cancer cells.
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Affiliation(s)
- Song-Hee Kim
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Byung-Chul Kang
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Daseul Seong
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Won-Hyeok Lee
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Jae-Hee An
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
| | - Hyoung-Uk Je
- Department of Radiation Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea;
| | - Hee-Jeong Cha
- Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea;
| | - Hyo-Won Chang
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (H.-W.C.); (S.-Y.K.)
| | - Sang-Yoon Kim
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (H.-W.C.); (S.-Y.K.)
| | - Seong-Who Kim
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Correspondence: (S.-W.K.); (M.-W.H.)
| | - Myung-Woul Han
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea; (S.-H.K.); (B.-C.K.); (D.S.); (W.-H.L.); (J.-H.A.)
- Correspondence: (S.-W.K.); (M.-W.H.)
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Zhong C, Li Y, Yang J, Jin S, Chen G, Li D, Fan X, Lin H. Immunotherapy for Hepatocellular Carcinoma: Current Limits and Prospects. Front Oncol 2021; 11:589680. [PMID: 33854960 PMCID: PMC8039369 DOI: 10.3389/fonc.2021.589680] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 03/10/2021] [Indexed: 12/13/2022] Open
Abstract
Although many approaches have been used to treat hepatocellular carcinoma (HCC), the clinical benefits remain limited, particularly for late stage HCC. In recent years, studies have focused on immunotherapy for HCC. Immunotherapies have shown promising clinical outcomes in several types of cancers and potential therapeutic effects for advanced HCC. In this review, we summarize the immune tolerance and immunotherapeutic strategies for HCC as well as the main challenges of current therapeutic approaches. We also present alternative strategies for overcoming these limitations.
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Affiliation(s)
- Cheng Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Yang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Guoqiao Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Duguang Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,State Key Laboratory of Modern Optical Instrumentations, Centre for Optical and Electromagnetic Research, College of Optical Science and Engineering, International Research Center for Advanced Photonics, Zhejiang University, Hangzhou, China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Zhao J, Li H, Zhao S, Wang E, Zhu J, Feng D, Zhu Y, Dou W, Fan Q, Hu J, Jia L, Liu L. Epigenetic silencing of miR-144/451a cluster contributes to HCC progression via paracrine HGF/MIF-mediated TAM remodeling. Mol Cancer 2021; 20:46. [PMID: 33658044 PMCID: PMC7927270 DOI: 10.1186/s12943-021-01343-5] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is among the malignancies with the highest mortality. The key regulators and their interactive network in HCC pathogenesis remain unclear. Along with genetic mutations, aberrant epigenetic paradigms, including deregulated microRNAs (miRNAs), exert profound impacts on hepatocyte transformation and tumor microenvironment remodeling; however, the underlying mechanisms are largely uncharacterized. METHODS We performed RNA sequencing on HCC specimens and bioinformatic analyses to identify tumor-associated miRNAs. The miRNA functional targets and their effects on tumor-infiltrating immune cells were investigated. The upstream events, particularly the epigenetic mechanisms responsible for miRNA deregulation in HCC, were explored. RESULTS The miR-144/miR-451a cluster was downregulated in HCC and predicted a better HCC patient prognosis. These miRNAs promoted macrophage M1 polarization and antitumor activity by targeting hepatocyte growth factor (HGF) and macrophage migration inhibitory factor (MIF). The miR-144/miR-451a cluster and EZH2, the catalytic subunit of polycomb repressive complex (PRC2), formed a feedback circuit in which miR-144 targeted EZH2 and PRC2 epigenetically repressed the miRNA genes via histone H3K27 methylation of the promoter. The miRNA cluster was coordinately silenced by distal enhancer hypermethylation, disrupting chromatin loop formation and enhancer-promoter interactions. Clinical examinations indicated that methylation of this chromatin region is a potential HCC biomarker. CONCLUSIONS Our study revealed novel mechanisms underlying miR-144/miR-451a cluster deregulation and the crosstalk between malignant cells and tumor-associated macrophages (TAMs) in HCC, providing new insights into HCC pathogenesis and diagnostic strategies.
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Affiliation(s)
- Junlong Zhao
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Development Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Huichen Li
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fourth Military Medical University, No.169 Changlexi Road, Xi'an, 710032, China
| | - Shoujie Zhao
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Enxin Wang
- Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, No.569 Xinsi Road, Xi'an, 710038, China
| | - Jun Zhu
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fourth Military Medical University, No.169 Changlexi Road, Xi'an, 710032, China
| | - Dayun Feng
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Yejing Zhu
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Weijia Dou
- Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, No.569 Xinsi Road, Xi'an, 710038, China
| | - Qingling Fan
- Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, No.569 Xinsi Road, Xi'an, 710038, China
| | - Jie Hu
- Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, No.569 Xinsi Road, Xi'an, 710038, China
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fourth Military Medical University, No.169 Changlexi Road, Xi'an, 710032, China.
| | - Lei Liu
- Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, No.569 Xinsi Road, Xi'an, 710038, China. .,Department of Cell Biology, Fourth Military Medical University, No.169 Changlexi Road, Xi'an, 710032, China.
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Atwa SM, Handoussa H, Hosny KM, Odenthal M, Tayebi HME. Pivotal role of long non-coding ribonucleic acid-X-inactive specific transcript in regulating immune checkpoint programmed death ligand 1 through a shared pathway between miR-194-5p and miR-155-5p in hepatocellular carcinoma. World J Hepatol 2020; 12:1211-1227. [PMID: 33442449 PMCID: PMC7772730 DOI: 10.4254/wjh.v12.i12.1211] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/30/2020] [Accepted: 10/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight. However, such therapy has a modest response in hepatocellular carcinoma (HCC). Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint blockade. Non-coding ribonucleic acid (ncRNA) driven regulation is a major mechanism of epigenetic modulation. Given the wide range of ncRNAs that co-opt in programmed cell-death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) regulation, and based on the literature, we hypothesized that miR-155-5p, miR-194-5p and long non-coding RNAs (lncRNAs) X-inactive specific transcript (XIST) and MALAT-1 are involved in a regulatory upstream pathway for PD-1/PD-L1. Recently, nutraceutical therapeutics in cancers have received increasing attention. Thus, it is interesting to study the impact of oleuropein on the respective study key players.
AIM To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/PD-L1.
METHODS Bioinformatics tools including microrna.org and lnCeDB software were adopted to detect targeting of miR-155-5p, miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA, respectively. In addition, Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and MALAT-1. HCC and normal tissue samples were collected for scanning of PD-L1, XIST and MALAT-1 expression. To study the interaction among miR-155-5p, miR-194-5p, lncRNAs XIST and MALAT-1, as well as PD-L1 mRNA, a series of transfections of the Huh-7 cell line was carried out.
RESULTS Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PD-L1, MALAT-1 and XIST. MALAT-1 and XIST were predicted to target PD-L1 mRNA. PD-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls; however, MALAT-1 was barely detected. MiR-194 induced expression elevated the expression of PD-L1, XIST and MALAT-1. However, overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST, while it had a negative impact on MALAT-1 expression. Knockdown of XIST did have an impact on PD-L1 expression; however, following knockdown of the negative regulator of X-inactive specific transcript (TSIX), PD-L1 expression was elevated, and abolished MALAT-1 activity. Upon co-transfection of miR-194-5p with siMALAT-1, PD-L1 expression was elevated. Co-transfection of miR-194-5p with siXIST did not have an impact on PD-L1 expression. Upon co-transfection of miR-194 with siTSIX, PD-L1 expression was upregulated. Interestingly, the same PD-L1 expression pattern was observed following miR-155-5p co-transfections. Oleuropein treatment of Huh-7 cells reduced the expression profile of PD-L1, XIST, and miR-155-5p, upregulated the expression of miR-194-5p and had no significant impact on the MALAT-1 expression profile.
CONCLUSION This study reported a novel finding revealing that opposing acting miRNAs in HCC, have the same impact on PD-1/PD-L1 immune checkpoint by sharing a common signaling pathway.
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Affiliation(s)
- Sara M Atwa
- Pharmaceutical Biology Department, German University in Cairo, Cairo 11865, Egypt
| | - Heba Handoussa
- Pharmaceutical Biology Department, German University in Cairo, Cairo 11865, Egypt
| | - Karim M Hosny
- Department of General Surgery, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | - Margarete Odenthal
- Institute for Pathology, University Hospital Cologne, Cologne 50924, Germany
| | - Hend M El Tayebi
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9593254. [PMID: 33299889 PMCID: PMC7707949 DOI: 10.1155/2020/9593254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/13/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most lethal, following lung cancer. Currently applied therapeutic practices rely on surgical resection, chemotherapy and radiotherapy, or a combination thereof. These treatment options are associated with extreme adversities, and risk/benefit ratios do not always work in patients' favor. Anomalies of the epigenome lie at the epicenter of aberrant molecular mechanisms by which the disease develops and progresses. Modulation of these anomalous events poses a promising prospect for alternative treatment options, with an abundance of felicitous results reported in recent years. Herein, the most recent epigenetic modulators in hepatocellular carcinoma are recapitulated on.
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Sajjadi E, Venetis K, Scatena C, Fusco N. Biomarkers for precision immunotherapy in the metastatic setting: hope or reality? Ecancermedicalscience 2020; 14:1150. [PMID: 33574895 PMCID: PMC7864694 DOI: 10.3332/ecancer.2020.1150] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Indexed: 12/12/2022] Open
Abstract
Precision immunotherapy is a crucial approach to improve the efficacy of anti-cancer treatments, particularly in the metastatic setting. In this respect, accurate patient selection takes advantage of the multidimensional integration of patients' clinical information and tumour-specific biomarkers status. Among these biomarkers, programmed death-ligand 1, tumour-infiltrating lymphocytes, microsatellite instability, mismatch repair and tumour mutational burden have been widely investigated. However, novel tumour-specific biomarkers and testing methods will further improve patients' outcomes. Here, we discuss the currently available strategies for the implementation of a precision immunotherapy approach in the clinical management of metastatic solid tumours and highlight future perspectives.
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Affiliation(s)
- Elham Sajjadi
- Divison of Pathology, European Institute of Oncology (IEO) IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Konstantinos Venetis
- Divison of Pathology, European Institute of Oncology (IEO) IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Cristian Scatena
- Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 57, 56126 Pisa, Italy
| | - Nicola Fusco
- Divison of Pathology, European Institute of Oncology (IEO) IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
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Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA. Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg. JHEP Rep 2020; 2:100167. [PMID: 33134907 PMCID: PMC7585149 DOI: 10.1016/j.jhepr.2020.100167] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/22/2020] [Accepted: 07/24/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.
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Key Words
- 5acC, 5-acetylcytosine
- 5fC, 5-formylcytosine
- 5hmC, 5-hydoxymethyl cytosine
- 5mC, 5-methylcytosine
- Acetyl-CoA, acetyl coenzyme A
- BER, base excision repair
- BRD, bromodomain
- CDA, cytidine deaminase
- CGI, CpG island
- CIMP, CGI methylator phenotype
- CTLA-4, cytotoxic T-lymphocyte-associated protein 4
- DNMT, DNA methyltransferase
- DNMTi, DNMT inhibitor
- Epigenetics
- FAD, flavin adenine dinucleotide
- HAT, histone acetyltransferases
- HCC, hepatocellular carcinoma
- HDAC, histone deacetylase
- HDACi, HDAC inhibitor
- HDM, histone demethylase
- HMT, histone methyltransferase
- Hepatocellular carcinoma
- KMT, lysine methyltransferase
- LSD/KDM, lysine specific demethylases
- NAFLD, non-alcoholic fatty liver disease
- NK, natural killer
- NPC, nasopharyngeal carcinoma
- PD-L1, programmed cell death ligand-1
- PD1, programmed cell death protein 1
- PHD, plant homeodomain
- PTM, post-translational modification
- SAM, S-adenosyl-L-methionine
- TDG, thymidine-DNA-glycosylase
- TERT, telomerase reverse transcriptase
- TET, ten-eleven translocation
- TME, tumour microenvironment
- TSG, tumour suppressor gene
- Therapy
- UHRF1, ubiquitin like with PHD and ring finger domains 1
- VEGF, vascular endothelial growth factor
- ncRNAs, non-coding RNAs
- α-KG, α-ketoglutarate
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Affiliation(s)
- Maite G. Fernández-Barrena
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - María Arechederra
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Leticia Colyn
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
| | - Carmen Berasain
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Matias A. Avila
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
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Hepatocellular carcinoma immunotherapy: The impact of epigenetic drugs and the gut microbiome. LIVER RESEARCH 2020; 4:191-198. [PMID: 33343967 PMCID: PMC7746137 DOI: 10.1016/j.livres.2020.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The incidence of hepatocellular carcinoma (HCC) has been increasing for decades. This disease has now risen to become the sixth most common malignancy overall, while ranking as the third most frequent cause of cancer mortality. While several surgical interventions and loco-regional treatment options are available, up to 80% of patients present with advanced disease not amenable to standard therapies. Indeed, traditional cytotoxic chemotherapeutic agents are notoriously ineffective and essentially play no role in the management of affected patients. This has led to an enormous need for more effective systemic therapeutic options. In recent years, immunotherapy has emerged as a potentially viable and exciting new alternative for the treatment of HCC. Although the current immunotherapeutic options remain imperfect, various strategies can be employed to further improve their efficacy. New findings have revealed epigenetic modulation can be effective as a new approach for improving HCC immunotherapy. Studying the gut microbiome (gut-liver axis) can also be an interesting subject in this regard. Here, we explore the latest insights into the role of immunotherapy treatmenting HCC, both mono and in combination with other agents. We also focus on the impact of epigenetic drugs and the microbiome in the overall effectiveness of HCC immunotherapy.
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47
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Kang N, Eccleston M, Clermont PL, Latarani M, Male DK, Wang Y, Crea F. EZH2 inhibition: a promising strategy to prevent cancer immune editing. Epigenomics 2020; 12:1457-1476. [PMID: 32938196 PMCID: PMC7607396 DOI: 10.2217/epi-2020-0186] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/28/2020] [Indexed: 02/06/2023] Open
Abstract
Immunotherapies are revolutionizing the clinical management of a wide range of cancers. However, intrinsic or acquired unresponsiveness to immunotherapies does occur due to the dynamic cancer immunoediting which ultimately leads to immune escape. The evolutionarily conserved histone modifier enhancer of zeste 2 (EZH2) is aberrantly overexpressed in a number of human cancers. Accumulating studies indicate that EZH2 is a main driver of cancer cells' immunoediting and mediate immune escape through downregulating immune recognition and activation, upregulating immune checkpoints and creating an immunosuppressive tumor microenvironment. In this review, we overviewed the roles of EZH2 in cancer immunoediting, the preclinical and clinical studies of current pharmacologic EZH2 inhibitors and the prospects for EZH2 inhibitor and immunotherapy combination for cancer treatment.
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Affiliation(s)
- Ning Kang
- Department of Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Mark Eccleston
- Belgian Volition SPRL, Parc Scientifique Créalys, Rue Phocas Lejeune 22, BE-5032 Isnes, Belgium
| | - Pier-Luc Clermont
- Faculty of Medicine, Université Laval, 1050, avenue de la Médecine, Québec, QC, G1V 0A6, Canada
| | - Maryam Latarani
- Cancer Research Group, School of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
| | - David Kingsley Male
- Cancer Research Group, School of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
| | - Yuzhuo Wang
- Department of Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
- Department of Urologic Sciences, The Vancouver Prostate Centre, The University of British Columbia, 2660 Oak St, Vancouver, BC, V6H 3Z6, Canada
| | - Francesco Crea
- Cancer Research Group, School of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
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48
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Jiang G, Shi L, Zheng X, Zhang X, Wu K, Liu B, Yan P, Liang X, Yu T, Wang Y, Cai X. Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma. Aging (Albany NY) 2020; 12:11466-11484. [PMID: 32579541 PMCID: PMC7343489 DOI: 10.18632/aging.103231] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/29/2020] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with gender-related differences in onset and course. Androgen receptor (AR), a male hormone receptor, is critical in the initiation and progression of HCC. The role of AR in HCC has been mechanistically characterized and anti-AR therapies have been developed, showing limited efficacy. Immunotherapy targeting immune checkpoint proteins may substantially improve the clinical management of HCC. The mechanism by which AR influences HCC immune state remains unclear. In this study, we demonstrated that AR negatively regulated PD-L1, by acting as a transcriptional repressor of PD-L1. Notably, AR over-expression in HCC cells enhanced CD8+T function in vitro. We then verified the AR/PD-L1 correlation in patients. In animal experiment we found that lower AR expressed tumor achieved better response to PD-L1 inhibitor. Thus, AR suppressed PD-L1 expression, possibly contributing to gender disparity in HCC. Better understanding of the roles of AR during HCC initiation and progression will provide a novel angle to develop potential HCC immunotherapies.
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Affiliation(s)
- Guangyi Jiang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liang Shi
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xueyong Zheng
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xinjie Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ke Wu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Boqiang Liu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Peijian Yan
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tunan Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yifan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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49
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Liu A, Wu Q, Peng D, Ares I, Anadón A, Lopez-Torres B, Martínez-Larrañaga MR, Wang X, Martínez MA. A novel strategy for the diagnosis, prognosis, treatment, and chemoresistance of hepatocellular carcinoma: DNA methylation. Med Res Rev 2020; 40:1973-2018. [PMID: 32525219 DOI: 10.1002/med.21696] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 04/29/2020] [Accepted: 05/17/2020] [Indexed: 12/11/2022]
Abstract
The cancer mortality rate of hepatocellular carcinoma (HCC) is the second highest in the world and the therapeutic options are limited. The incidence of this deadly cancer is rising at an alarming rate because of the high degree of resistance to chemo- and radiotherapy, lack of proper, and adequate vaccination to hepatitis B, and lack of consciousness and knowledge about the disease itself and the lifestyle of the people. DNA methylation and DNA methylation-induced epigenetic alterations, due to their potential reversibility, open the access to develop novel biomarkers and therapeutics for HCC. The contribution to these epigenetic changes in HCC development still has not been thoroughly summarized. Thus, it is necessary to better understand the new molecular targets of HCC epigenetics in HCC diagnosis, prevention, and treatment. This review elaborates on recent key findings regarding molecular biomarkers for HCC early diagnosis, prognosis, and treatment. Currently emerging epigenetic drugs for the treatment of HCC are summarized. In addition, combining epigenetic drugs with nonepigenetic drugs for HCC treatment is also mentioned. The molecular mechanisms of DNA methylation-mediated HCC resistance are reviewed, providing some insights into the difficulty of treating liver cancer and anticancer drug development.
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Affiliation(s)
- Aimei Liu
- National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University (HZAU), Wuhan, China
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, China.,Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Dapeng Peng
- National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University (HZAU), Wuhan, China
| | - Irma Ares
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Research Institute Hospital 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Arturo Anadón
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Research Institute Hospital 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Bernardo Lopez-Torres
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Research Institute Hospital 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - María-Rosa Martínez-Larrañaga
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Research Institute Hospital 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University (HZAU), Wuhan, China.,Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Research Institute Hospital 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - María-Aránzazu Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Research Institute Hospital 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Madrid, Spain
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50
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Richart L, Margueron R. Drugging histone methyltransferases in cancer. Curr Opin Chem Biol 2020; 56:51-62. [DOI: 10.1016/j.cbpa.2019.11.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023]
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