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Zhong R, Qiu C, Chan S, Wang Y, Liu K, Xia Y, Zhang H, Zou B. TDH-11 inhibits the proliferation and colonization of colorectal cancer by reducing the activity of HDAC. Cell Signal 2025; 132:111817. [PMID: 40250693 DOI: 10.1016/j.cellsig.2025.111817] [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: 12/17/2024] [Revised: 03/28/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025]
Abstract
Histone deacetylase inhibitors (HDACIs) have demonstrated significant efficacy and minimal toxic side effects in certain hematological tumors. Nevertheless, their utilization in the therapy of solid tumors, including colorectal cancer (CRC), is constrained by the occurrence of adverse effects such as myelosuppression and cardiotoxicity. Therefore, the development of more efficient and safer HDACIs is crucial for managing CRC. Here, the effects of TDH-11 (a novel HDAC inhibitor) and the underlying molecular mechanisms that inhibits the deveolpment and progression of CRC cells were investigated using in vitro and in vivo experiments. The results indicated that TDH-11 inhibited CRC tumorigenic behavior while also promoted apoptosis and cell cycle arrest. In vivo, TDH-11 markedly inhibited tumor progression and reduces tumor colonization without causing substantial damage to key organs, such as the kidneys, heart, lungs, spleen, and liver. Results of RNA sequencing and western blot suggested that TDH-11 exerted its antitumor effects through modulation of the p53 signaling pathway and its downstream pathways involved in apoptosis and cell cycle regulation. In summary, TDH-11 exhibited significant potential in suppressing the growth and colonization of CRC, as determined in both cellular and animal models. These results provided novel insights into CRC-associated pathways and suggest promising prospects for managing advanced and metastatic CRC.
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Affiliation(s)
- Rulei Zhong
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Chenyang Qiu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Shixin Chan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yiming Wang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Kaige Liu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yihui Xia
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Huabing Zhang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui, China; Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Bingbing Zou
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China.
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Chen YM, Yang WQ, Fan YY, Chen Z, Liu YZ, Zhao BS. Trichostatin A augments cell migration and epithelial-mesenchymal transition in esophageal squamous cell carcinoma through BRD4/ c-Myc endoplasmic reticulum-stress pathway. World J Gastroenterol 2025; 31:103449. [PMID: 40124272 PMCID: PMC11924005 DOI: 10.3748/wjg.v31.i11.103449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/09/2025] [Accepted: 02/14/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND The causes of death in patients with advanced esophageal cancer are multifactorial, with tumor metastasis being one of the important factors. Histone acetylation promotes the migration of esophageal squamous cell carcinoma (ESCC) cells, while the histone deacetylase inhibitor (HDACi) shows complex effects on tumor functions. AIM To comprehensively elucidate the impact and molecular mechanisms of trichostatin A (TSA), an HDACi, on cell migration in ESCC through bromodomain-containing protein (BRD4)/cellular myelocytomatosis oncogene (c-Myc)/endoplasmic reticulum (ER)-stress. METHODS The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays, with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms. The mRNA levels involved were examined by quantitative real-time polymerase chain reaction. Protein levels of acetylated histones H3 (acH3) and acetylated histones H4, BRD4, c-Myc, as well as markers of ER stress and epithelial-mesenchymal transition (EMT), were analyzed using western blot. Additionally, this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues. Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis. RESULTS TSA promoted the migration of ESCC cells by stimulating the EMT process. TSA-mediated histone acetylation facilitated the recruitment of BRD4, a bromodomain-containing protein, triggering the expression of c-Myc. This cascade induced ER stress and enhanced EMT in ESCC cells. To further elucidate the underlying mechanism, we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid, knockdown of c-Myc and BRD4 expression, and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1. Mechanistically, these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4, which in turn triggered the expression of c-Myc. This sequential activation induced ER stress and subsequently enhanced EMT, thereby promoting the migration of ESCC cells. Additionally, we examined histone acetylation levels in specimens from 43 patients with ESCC, including both tumor tissues and paired adjacent tissues. Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC. CONCLUSION TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway. Moreover, elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis. These findings enhance our understanding of ESCC migration and HDACi therapy.
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Affiliation(s)
- Yan-Min Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Department of Oncology, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo 454000, Henan Province, China
| | - Wen-Qian Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Henan Medical Science Key Laboratory of Esophageal Cancer Metastasis Translational Medicine, Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Ying-Ying Fan
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Zhi Chen
- Department of Anesthesiology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Yu-Zhen Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Henan Medical Science Key Laboratory of Esophageal Cancer Metastasis Translational Medicine, Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Bao-Sheng Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Henan Medical Science Key Laboratory of Esophageal Cancer Metastasis Translational Medicine, Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
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Tang J, Chen H, Fan H, Chen T, Pu C, Guo Y. Research progress of BRD4 in head and neck squamous cell carcinoma: Therapeutic application of novel strategies and mechanisms. Bioorg Med Chem 2024; 113:117929. [PMID: 39317007 DOI: 10.1016/j.bmc.2024.117929] [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: 07/24/2024] [Revised: 09/09/2024] [Accepted: 09/15/2024] [Indexed: 09/26/2024]
Abstract
Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extra-terminal domain (BET) protein family, which plays a crucial role in recognizing acetylated lysine residues in chromatin. The abnormal expression of BRD4 contributes to the development of various human malignant tumors, including head and neck squamous cell carcinoma (HNSCC). Recent studies have shown that BRD4 inhibition can effectively prevent the proliferation and growth of HNSCC. However, the specific role and mechanism of BRD4 in HNSCC are not yet fully clarified. This article will briefly summarize the critical role of BRD4 in the pathogenesis of HNSCC and discuss the potential clinical applications of targeting BRD4 in HNSCC therapy. We further inquiry the challenges and opportunities for HNSCC therapies based on BRD4 inhibition, including BRD4 inhibitor combination with conventional chemotherapy, radiotherapy, and immunotherapy, as well as new strategies of BRD4-targeting drugs and BRD4 proteolysis-targeting chimeras (PROTACs). Moreover, we will also offer outlook on the associated challenges and future directions of targeting BRD4 for the treatment of patients with HNSCC.
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Affiliation(s)
- Jiao Tang
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Department of Laboratory Medicine, Xindu District People's Hospital, Chengdu, Sichuan 610500, China
| | - Huaqiu Chen
- Department of Laboratory Medicine, Xichang People's Hospital, Xichang, Sichuan 615000, China
| | - Hengrui Fan
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China
| | - Tao Chen
- Department of Laboratory Medicine, Xindu District People's Hospital, Chengdu, Sichuan 610500, China
| | - Chunlan Pu
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China.
| | - Yuanbiao Guo
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China.
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Wang Z, Chen G, Yuan D, Wu P, Guo J, Lu Y, Wang Z. Caveolin-1 promotes glioma proliferation and metastasis by enhancing EMT via mediating PAI-1 activation and its correlation with immune infiltrates. Heliyon 2024; 10:e24464. [PMID: 38298655 PMCID: PMC10827802 DOI: 10.1016/j.heliyon.2024.e24464] [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: 11/08/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 02/02/2024] Open
Abstract
Glioma is typically characterized by a poor prognosis and is associated with a decline in the quality of life as the disease advances. However, the development of effective therapies for glioma has been inadequate. Caveolin-1 (CAV-1) is a membrane protein that plays a role in caveolae formation and interacts with numerous signaling proteins, compartmentalizing them in caveolae and frequently exerting direct control over their activity through binding to its scaffolding domain. Although CAV-1 is a vital regulator of tumour progression, its role in glioma remains unclear. Our findings indicated that the knockdown of CAV-1 significantly inhibits the proliferation and metastasis of glioma. Subsequent mechanistic investigations demonstrated that CAV-1 promotes proliferation and metastasis by activating the photoshatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Furthermore, we demonstrated that CAV-1 overexpression upregulates the expression of serpin peptidase inhibitor, class E, member 1 (SERPINE1, also known as PAI-1), which serves as a marker for the epithelial-mesenchymal transition (EMT) process. Further research showed that PAI-1 knockdown abolished the CAV-1 mediated activation of PI3K/Akt signaling pathway. In glioma tissues, CAV-1 expression exhibited a correlation with unfavorable prognosis and immune infiltration among glioma patients. In summary, our study provided evidence that CAV-1 activates the PI3K/Akt signaling pathway by upregulating PAI-1, thereby promoting the proliferation and metastasis of glioma through enhanced epithelial-mesenchymal transition (EMT) and angiogenesis, and CAV-1 is involved in the immune infiltration.
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Affiliation(s)
- Zhaoxiang Wang
- Department of Neurosurgery, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
- Department of Neurosurgery, The First People's Hospital of Yancheng, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
| | - Gang Chen
- Department of Neurosurgery, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
- Department of Neurosurgery, The First People's Hospital of Yancheng, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
| | - Debin Yuan
- Department of Neurosurgery, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
- Department of Neurosurgery, The First People's Hospital of Yancheng, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
| | - Peizhang Wu
- Department of Neurosurgery, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
- Department of Neurosurgery, The First People's Hospital of Yancheng, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
| | - Jun Guo
- Department of Neurosurgery, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
- Department of Neurosurgery, The First People's Hospital of Yancheng, No. 166 Yulong West Road, Yancheng, 224000, Jiangsu, China
| | - Yisheng Lu
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong University, Jiangsu, 226001, China
| | - Zhenyu Wang
- Department of Pediatric General Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiaotong University, No. 355 Luding Road, Shanghai, 200062, Shanghai, China
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Ahuja P, Yadav R, Goyal S, Yadav C, Ranga S, Kadian L. Targeting epigenetic deregulations for the management of esophageal carcinoma: recent advances and emerging approaches. Cell Biol Toxicol 2023; 39:2437-2465. [PMID: 37338772 DOI: 10.1007/s10565-023-09818-5] [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: 03/16/2023] [Accepted: 06/08/2023] [Indexed: 06/21/2023]
Abstract
Ranking from seventh in incidence to sixth in mortality, esophageal carcinoma is considered a severe malignancy of food pipe. Later-stage diagnosis, drug resistance, and a high mortality rate contribute to its lethality. Esophageal squamous cell carcinoma and esophageal adenocarcinoma are the two main histological subtypes of esophageal carcinoma, with squamous cell carcinoma alone accounting for more than eighty percent of its cases. While genetic anomalies are well known in esophageal cancer, accountability of epigenetic deregulations is also being explored for the recent two decades. DNA methylation, histone modifications, and functional non-coding RNAs are the crucial epigenetic players involved in the modulation of different malignancies, including esophageal carcinoma. Targeting these epigenetic aberrations will provide new insights into the development of biomarker tools for risk stratification, early diagnosis, and effective therapeutic intervention. This review discusses different epigenetic alterations, emphasizing the most significant developments in esophageal cancer epigenetics and their potential implication for the detection, prognosis, and treatment of esophageal carcinoma. Further, the preclinical and clinical status of various epigenetic drugs has also been reviewed.
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Affiliation(s)
- Parul Ahuja
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Ritu Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India.
| | - Sandeep Goyal
- Department of Internal Medicine, Pt. B.D, Sharma University of Health Sciences, (Haryana), Rohtak, 124001, India
| | - Chetna Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Shalu Ranga
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Lokesh Kadian
- Department of Dermatology, School of Medicine, Indiana University, Indianapolis, Indiana, 46202, USA
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Kielbik M, Przygodzka P, Szulc-Kielbik I, Klink M. Snail transcription factors as key regulators of chemoresistance, stemness and metastasis of ovarian cancer cells. Biochim Biophys Acta Rev Cancer 2023; 1878:189003. [PMID: 37863122 DOI: 10.1016/j.bbcan.2023.189003] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/13/2023] [Accepted: 10/14/2023] [Indexed: 10/22/2023]
Abstract
Ovarian cancer is one of the deadliest gynecological malignancies among women. The reason for this outcome is the frequent acquisition of cancer cell resistance to platinum-based drugs and unresponsiveness to standard therapy. It has been increasingly recognized that the ability of ovarian cancer cells to adopt more aggressive behavior (mainly through the epithelial-to-mesenchymal transition, EMT), as well as dedifferentiation into cancer stem cells, significantly affects drug resistance acquisition. Transcription factors in the Snail family have been implicated in ovarian cancer chemoresistance and metastasis. In this article, we summarize published data that reveal Snail proteins not only as key inducers of the EMT in ovarian cancer but also as crucial links between the acquisition of ovarian cancer stem properties and spheroid formation. These Snail-related characteristics significantly affect the ovarian cancer cell response to treatment and are related to the acquisition of chemoresistance.
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Affiliation(s)
- Michal Kielbik
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland
| | - Patrycja Przygodzka
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland
| | - Izabela Szulc-Kielbik
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland
| | - Magdalena Klink
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland.
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Yang WQ, Liang R, Gao MQ, Liu YZ, Qi B, Zhao BS. Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy. World J Gastrointest Oncol 2022; 14:2340-2352. [PMID: 36568944 PMCID: PMC9782615 DOI: 10.4251/wjgo.v14.i12.2340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/17/2022] [Accepted: 11/16/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC), the predominant type of esophageal cancer, has a 5-year survival rate less than 20%. Although the cause of poor prognosis is the high incidence and mortality of ESCC, the high rate of metastasis after esophageal cancer surgery is the main cause of death after the surgery. Bromodomain-containing protein 4 (BRD4), an epigenetic reader of chromatin-acetylated histones in tumorigenesis and development, plays an essential role in regulating oncogene expression. BRD4 inhibition and BRD4 inhibition-based treatment can potentially suppress ESCC growth. However, the effects and mechanisms of action of BRD4 on ESCC cell migration remain unclear.
AIM To explore the effect of BRD4 on cell migration of ESCC in vitro and its possible molecular mechanism.
METHODS Human ESCC cell lines KYSE-450 and KYSE-150 were used. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay was performed to examine cell proliferation, and the transwell migration assay was conducted to test ESCC cell migration. JQ1, a BRD4 inhibitor, was applied to cells, and BRD4 siRNA was transfected into ESCC cells to knockdown endogenous BRD4. GFP-RFP-LC3 adenovirus was infected into ESCC cells to evaluate the effect of JQ1 on autophagy. Western blotting was performed to determine the protein levels of BRD4, E-cadherin, vimentin, AMP-activated protein kinase (AMPK), and p-AMPK.
RESULTS BRD4 was either downregulated by small interfering RNA or pretreated with JQ1 in ESCC cells, leading to increased tumor migration in ESCC cells in a dose- and time-dependent manner. Inhibition of BRD4 not only significantly suppressed cell proliferation but also strongly increased cell migration by inducing epithelial-mesenchymal transition (EMT). The protein expression of vimentin was increased and E-cadherin decreased in a dose-dependent manner, subsequently promoting autophagy in KYSE-450 and KYSE-150 cells. Pretreatment with JQ1, a BRD4 inhibitor, inhibited BRD4-induced LC3-II activation and upregulated AMPK phosphorylation in a dose-dependent manner. Additionally, an increased number of autophagosomes and autolysosomes were observed in JQ1-treated ESCC cells. The autophagy inhibitor 3-methyladenine (3-MA) reversed the effects of BRD4 knockdown on ESCC cell migration and blocked JQ1-induced cell migration. 3-MA also downregulated the expression of vimentin and upregulation E-cadherin.
CONCLUSION BRD4 inhibition enhances cell migration by inducing EMT and autophagy in ESCC cells via the AMPK-modified pathway. Thus, the facilitating role on ESCC cell migration should be considered for BRD4 inhibitor clinical application to ESCC patients.
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Affiliation(s)
- Wen-Qian Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Esophageal Cancer Institute, Xinxiang Medical University, Weihui 453100, Henan Province, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Rui Liang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Esophageal Cancer Institute, Xinxiang Medical University, Weihui 453100, Henan Province, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Man-Qi Gao
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Esophageal Cancer Institute, Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Yu-Zhen Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Esophageal Cancer Institute, Xinxiang Medical University, Weihui 453100, Henan Province, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Bo Qi
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Bao-Sheng Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Esophageal Cancer Institute, Xinxiang Medical University, Weihui 453100, Henan Province, China
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Bouyahya A, El Omari N, Bakha M, Aanniz T, El Menyiy N, El Hachlafi N, El Baaboua A, El-Shazly M, Alshahrani MM, Al Awadh AA, Lee LH, Benali T, Mubarak MS. Pharmacological Properties of Trichostatin A, Focusing on the Anticancer Potential: A Comprehensive Review. Pharmaceuticals (Basel) 2022; 15:ph15101235. [PMID: 36297347 PMCID: PMC9612318 DOI: 10.3390/ph15101235] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/12/2022] [Accepted: 09/23/2022] [Indexed: 11/05/2022] Open
Abstract
Trichostatin A (TSA), a natural derivative of dienohydroxamic acid derived from a fungal metabolite, exhibits various biological activities. It exerts antidiabetic activity and reverses high glucose levels caused by the downregulation of brain-derived neurotrophic factor (BDNF) expression in Schwann cells, anti-inflammatory activity by suppressing the expression of various cytokines, and significant antioxidant activity by suppressing oxidative stress through multiple mechanisms. Most importantly, TSA exhibits potent inhibitory activity against different types of cancer through different pathways. The anticancer activity of TSA appeared in many in vitro and in vivo investigations that involved various cell lines and animal models. Indeed, TSA exhibits anticancer properties alone or in combination with other drugs used in chemotherapy. It induces sensitivity of some human cancers toward chemotherapeutical drugs. TSA also exhibits its action on epigenetic modulators involved in cell transformation, and therefore it is considered an epidrug candidate for cancer therapy. Accordingly, this work presents a comprehensive review of the most recent developments in utilizing this natural compound for the prevention, management, and treatment of various diseases, including cancer, along with the multiple mechanisms of action. In addition, this review summarizes the most recent and relevant literature that deals with the use of TSA as a therapeutic agent against various diseases, emphasizing its anticancer potential and the anticancer molecular mechanisms. Moreover, TSA has not been involved in toxicological effects on normal cells. Furthermore, this work highlights the potential utilization of TSA as a complementary or alternative medicine for preventing and treating cancer, alone or in combination with other anticancer drugs.
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Affiliation(s)
- Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat 10106, Morocco
- Correspondence: (A.B.); (L.-H.L.); (M.S.M.)
| | - Nasreddine El Omari
- Laboratory of Histology, Embryology, and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10100, Morocco
| | - Mohamed Bakha
- Unit of Plant Biotechnology and Sustainable Development of Natural Resources “B2DRN”, Polydisciplinary Faculty of Beni Mellal, Sultan Moulay Slimane University, Mghila, P.O. Box 592, Beni Mellal 23000, Morocco
| | - Tarik Aanniz
- Medical Biotechnology Laboratory, Rabat Medical & Pharmacy School, Mohammed V University in Rabat, Rabat B.P. 6203, Morocco
| | - Naoual El Menyiy
- Laboratory of Pharmacology, National Agency of Medicinal and Aromatic Plants, Taounate 34025, Morocco
| | - Naoufal El Hachlafi
- Microbial Biotechnology and Bioactive Molecules Laboratory, Sciences and Technologies Faculty, Sidi Mohmed Ben Abdellah University, Imouzzer Road Fez, Fez 30050, Morocco
| | - Aicha El Baaboua
- Biotechnology and Applied Microbiology Team, Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan 93000, Morocco
| | - Mohamed El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo 11566, Egypt
| | - Mohammed Merae Alshahrani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia
| | - Ahmed Abdullah Al Awadh
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery Research Group (NBDD), Microbiome and Bioresource Research Strength (MBRS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Malaysia
- Correspondence: (A.B.); (L.-H.L.); (M.S.M.)
| | - Taoufiq Benali
- Environment and Health Team, Polydisciplinary Faculty of Safi, Cadi Ayyad University, Sidi Bouzid B.P. 4162, Morocco
| | - Mohammad S. Mubarak
- Department of Chemistry, The University of Jordan, Amma 11942, Jordan
- Correspondence: (A.B.); (L.-H.L.); (M.S.M.)
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Xu QR, Du XH, Huang TT, Zheng YC, Li YL, Huang DY, Dai HQ, Li EM, Fang WK. Role of Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma. Biomolecules 2022; 12:biom12101378. [PMID: 36291586 PMCID: PMC9599896 DOI: 10.3390/biom12101378] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.
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Affiliation(s)
| | | | | | | | | | | | | | - En-Min Li
- Correspondence: (E.-M.L.); (W.-K.F.)
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Chen J, Chen X, Li T, Wang L, Lin G. Identification of chromatin organization-related gene signature for hepatocellular carcinoma prognosis and predicting immunotherapy response. Int Immunopharmacol 2022; 109:108866. [PMID: 35691273 DOI: 10.1016/j.intimp.2022.108866] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 04/26/2022] [Accepted: 05/12/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chromatin organization is associated with tumorigenesis; however, information on its role in hepatocellular carcinoma (HCC) is limited. Moreover, although immune checkpoint inhibitors (ICIs) have proven effective against HCC, the optimal index remains unknown. In this study, we aimed to construct a chromatin organization-related gene signature (CORGS) for prognosis and predicting response to ICIs in HCC. METHODS HCC-related data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Construction (ICGC). Chromatin organization-related genes (CORGs) were retrieved from Gene Set Enrichment Analysis. Differentially expressed genes (DEGs) and prognostic genes were then applied to select candidate genes using advanced statistical methods, including learning vector quantization, random forest, and lasso regression. Subsequently, the CORGS was established based on chromatin organization-related hub genes using multivariate Cox regression analysis, evaluated with Kaplan-Meier survival curves, and verified in 64 samples of HCC patients from Fujian Provincial Hospital (FPH) via quantitative PCR. Subsequently, functional enrichment analysis, tumor somatic mutation analysis, and tumor immune analysis were performed to evaluate the potential value of the CORGS. RESULTS Three hundred and thirty-nine CORGs were identified as DEGs, and 186 were associated with HCC prognosis (all P < 0.05). Four intersection genes were selected to establish the CORGS using TCGA cohort, which was found to serve as an independent risk factor for HCC patients. CORGS was then validated in an ICGC cohort. In addition, CORGS reliability was verified in 64 samples from HCC patients and 26 adjacent non-tumorous tissues, collected from the FPH. The CORGS was also associated with tumor immune microenvironment characteristics and ICI response. Moreover, data from "IMvigor 210" revealed that more patients in the low CORGS group responded to atezolizumab compared to high CORGS patients (P < 0.05). Finally, a nomogram of tumor characteristics and the CORGS was established, exhibiting superior discrimination and calibration compared to the current staging system and published models. CONCLUSIONS CORGS may serve as an effective predictive biomarker for HCC as well as a potential index of the tumor immune microenvironment and ICI response.
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Affiliation(s)
- Jingbo Chen
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Xingte Chen
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Ting Li
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Lei Wang
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China; Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China.
| | - Guishan Lin
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China.
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Yao Z, Lin A, Yi Y, Shen W, Zhang J, Luo P. THSD7B Mutation Induces Platinum Resistance in Small Cell Lung Cancer Patients. Drug Des Devel Ther 2022; 16:1679-1695. [PMID: 35685767 PMCID: PMC9172928 DOI: 10.2147/dddt.s363665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 05/07/2022] [Indexed: 11/30/2022] Open
Abstract
Aim Several cases of small cell lung cancer (SCLC) patients demonstrate resistance to the treatment initiatives such as cisplatin after platinum chemotherapy. It is crucial to the improvement of the overall survival (OS) of SCLC patients to discover the gene mutation inducing platinum resistance within this cohort. Patients and Methods We analyzed the gene mutations significantly associated with the OS from 2 cohorts of SCLC platinum-treated patients. And then we screened out THSD7B mutation. In order to understand the mechanism between THSD7B mutation and platinum resistance, we designed gene mutation co-occurrence and mutual exclusivity analysis, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) analysis, and Connectivity Map (CMap) analysis. Results The poor prognosis of THSD7B mutant patients may be related to the inhibition of cell death-related pathways, the up-regulation of cell invasion and metastasis pathways, and the down-regulation of immune response pathways. Lovastatin and cyclooxygenase inhibitors could be used as potential target compounds in THSD7B mutant patients, which provides reference for future research on platinum resistance. Conclusion THSD7B can be considered a reliable biomarker that effectively facilitates the prediction of poor survival in SCLC platinum-treated patients.
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Affiliation(s)
- Zifu Yao
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China
- The First Clinical Medical School, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China
| | - Yonglin Yi
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China
| | - Weitao Shen
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China
- Correspondence: Jian Zhang; Peng Luo, Email ;
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China
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Kong F, Ma L, Wang X, You H, Zheng K, Tang R. Regulation of epithelial-mesenchymal transition by protein lysine acetylation. Cell Commun Signal 2022; 20:57. [PMID: 35484625 PMCID: PMC9052664 DOI: 10.1186/s12964-022-00870-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/20/2022] [Indexed: 01/01/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a vital driver of tumor progression. It is a well-known and complex trans-differentiation process in which epithelial cells undergo morphogenetic changes with loss of apical-basal polarity, but acquire spindle-shaped mesenchymal phenotypes. Lysine acetylation is a type of protein modification that favors reversibly altering the structure and function of target molecules via the modulation of lysine acetyltransferases (KATs), as well as lysine deacetylases (KDACs). To date, research has found that histones and non-histone proteins can be acetylated to facilitate EMT. Interestingly, histone acetylation is a type of epigenetic regulation that is capable of modulating the acetylation levels of distinct histones at the promoters of EMT-related markers, EMT-inducing transcription factors (EMT-TFs), and EMT-related long non-coding RNAs to control EMT. However, non-histone acetylation is a post-translational modification, and its effect on EMT mainly relies on modulating the acetylation of EMT marker proteins, EMT-TFs, and EMT-related signal transduction molecules. In addition, several inhibitors against KATs and KDACs have been developed, some of which can suppress the development of different cancers by targeting EMT. In this review, we discuss the complex biological roles and molecular mechanisms underlying histone acetylation and non-histone protein acetylation in the control of EMT, highlighting lysine acetylation as potential strategy for the treatment of cancer through the regulation of EMT.
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