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1
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Li L, Song Q, Zhou J, Ji Q. Controllers of histone methylation-modifying enzymes in gastrointestinal cancers. Biomed Pharmacother 2024; 174:116488. [PMID: 38520871 DOI: 10.1016/j.biopha.2024.116488] [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: 11/23/2023] [Revised: 02/26/2024] [Accepted: 03/19/2024] [Indexed: 03/25/2024] Open
Abstract
Gastrointestinal (GI) cancers have been considered primarily genetic malignancies, caused by a series of progressive genetic alterations. Accumulating evidence shows that histone methylation, an epigenetic modification program, plays an essential role in the different pathological stages of GI cancer progression, such as precancerous lesions, tumorigenesis, and tumor metastasis. Histone methylation-modifying enzymes, including histone methyltransferases (HMTs) and demethylases (HDMs), are the main executor of post-transcriptional modification. The abnormal expression of histone methylation-modifying enzymes characterizes GI cancers with complex pathogenesis and progression. Interactions between upstream controllers and histone methylation-modifying enzymes have recently been revealed, and have provided numerous opportunities to elucidate the pathogenesis of GI cancers in depth and clearly. Here we focus on the association between histone methylation-modifying enzymes and their controllers, aiming to provide a new perspective on the molecular research and clinical management of GI cancers.
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Affiliation(s)
- Ling Li
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qing Song
- Department of Medical Oncology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu 215007, China
| | - Jing Zhou
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Liver Disease Department of Integrative Medicine, Ningbo No.2 Hospital, Ningbo, Zhejiang 315000, China.
| | - Qing Ji
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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2
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Emerging role of G9a in cancer stemness and promises as a therapeutic target. Oncogenesis 2021; 10:76. [PMID: 34775469 PMCID: PMC8590690 DOI: 10.1038/s41389-021-00370-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/25/2021] [Accepted: 10/28/2021] [Indexed: 12/13/2022] Open
Abstract
The histone methyltransferase G9a is well-documented for its implication in neoplastic growth. However, recent investigations have demonstrated a key involvement of this chromatin writer in maintaining the self-renewal and tumor-initiating capacities of cancer stem cells (CSCs). Direct inhibition of G9a’s catalytic activity was reported as a promising therapeutic target in multiple preclinical studies. Yet, none of the available pharmacological inhibitors of G9a activity have shown success at the early stages of clinical testing. Here, we discuss central findings of oncogenic expression and activation of G9a in CSCs from different origins, as well as the impact of the suppression of G9a histone methyltransferase activity in such contexts. We will explore the challenges posed by direct and systemic inhibition of G9a activity in the perspective of clinical translation of documented small molecules. Finally, we will discuss recent advances in drug discovery as viable strategies to develop context-specific drugs, selectively targeting G9a in CSC populations.
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3
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Chen Y, Zhang C, Zou X, Yu M, Yang B, Ji CF, Gao SY, Li J, Liu B. Identification of macrophage related gene in colorectal cancer patients and their functional roles. BMC Med Genomics 2021; 14:159. [PMID: 34120619 PMCID: PMC8201885 DOI: 10.1186/s12920-021-01010-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 06/08/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Recent scientific research has enabled the identification of macrophages related-genes (MaRG), which play a key role in the control of the immune microenvironment in many human cancers. However, the functional role of MaRGs in human tumors is ill-defined. Herein, we aimed at bioinformatically exploring the molecular signatures of MaRGs in colorectal cancer. METHODS A list of MaRGs was generated and their differential expression was analyzed across multiple datasets downloaded from the publicly available functional genomics database Gene Expression Omnibus. The weighted gene co-expression network analysis (WGCNA) was also applied to identify the partner genes of these MaRGs in colorectal cancer. RESULTS After integration of the results from analyses of different datasets, we found that 29 differentially expressed MaRGs (DE-MaRGs) could be considered as CRC-related genes as obtained from the WGCNA analysis. These genes were functionally involved in positive regulation of DNA biosynthetic process and glutathione metabolism. Protein-protein interaction network analysis indicated that PDIA6, PSMA1, PRC1, RRM2, HSP90AB1, CDK4, MCM7, RFC4, and CCT5 were the hub MaRGs. The LASSO approach was used for validating the 29 MaRGs in TCGA-COAD and TCGA-READ data and the results showed that ten among the 29 genes could be considered as MaRGs significantly involved in CRC. The maftools analysis showed that MaRGs were mutated at varying degrees. The nomogram analysis indicated the correlation of these MaRGs with diverse clinical features of CRC patients. CONCLUSIONS Conclusively, the present disclosed a signature of MaRGs as potential key regulators involved in CRC pathogenesis and progression. These findings contribute not only to the understanding of the molecular mechanism of CRC pathogenesis but also to the development of adequate immunotherapies for CRC patients.
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Affiliation(s)
- Yingxiang Chen
- Engineering Research Center for Medicine, Harbin University of Commerce, Harbin, 150076 China
| | - Cui Zhang
- College of Pharmacy, Harbin University of Commerce, No. 138 Tongda Street, Harbin, 150076 Heilongjiang Province China
| | - Xiang Zou
- Engineering Research Center for Medicine, Harbin University of Commerce, Harbin, 150076 China
| | - Miao Yu
- Engineering Research Center for Medicine, Harbin University of Commerce, Harbin, 150076 China
| | - Bo Yang
- College of Pharmacy, Harbin University of Commerce, No. 138 Tongda Street, Harbin, 150076 Heilongjiang Province China
| | - Chen-Feng Ji
- Engineering Research Center for Medicine, Harbin University of Commerce, Harbin, 150076 China
| | - Shi-Yong Gao
- Engineering Research Center for Medicine, Harbin University of Commerce, Harbin, 150076 China
| | - Jun Li
- Engineering Research Center for Medicine, Harbin University of Commerce, Harbin, 150076 China
| | - Bin Liu
- Engineering Research Center for Medicine, Harbin University of Commerce, Harbin, 150076 China
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4
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G9a Is SETting the Stage for Colorectal Oncogenesis. Genes (Basel) 2020; 11:genes11060616. [PMID: 32512705 PMCID: PMC7349591 DOI: 10.3390/genes11060616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/31/2020] [Accepted: 06/02/2020] [Indexed: 12/28/2022] Open
Abstract
Recently, Kato et al. reported recurrent activating mutations in the SET domain of histone methyltransferase G9a, driving an oncogenic cascade in melanoma. The authors also reported correlations between G9a expression and the regulation of the canonical WNT pathway. Although we could not observe such mutations in human colorectal adenocarcinoma, newly reported findings are of high relevance to colorectal cancer, as WNT target gene signatures were closely associated with G9a expression. Here, we put into perspective such new results on G9a expression in colorectal cancers and the potential relationship with tumor heterogeneity and acquisition of neoplastic stemness.
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Wuputra K, Ku CC, Wu DC, Lin YC, Saito S, Yokoyama KK. Prevention of tumor risk associated with the reprogramming of human pluripotent stem cells. J Exp Clin Cancer Res 2020; 39:100. [PMID: 32493501 PMCID: PMC7268627 DOI: 10.1186/s13046-020-01584-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023] Open
Abstract
Human pluripotent embryonic stem cells have two special features: self-renewal and pluripotency. It is important to understand the properties of pluripotent stem cells and reprogrammed stem cells. One of the major problems is the risk of reprogrammed stem cells developing into tumors. To understand the process of differentiation through which stem cells develop into cancer cells, investigators have attempted to identify the key factors that generate tumors in humans. The most effective method for the prevention of tumorigenesis is the exclusion of cancer cells during cell reprogramming. The risk of cancer formation is dependent on mutations of oncogenes and tumor suppressor genes during the conversion of stem cells to cancer cells and on the environmental effects of pluripotent stem cells. Dissecting the processes of epigenetic regulation and chromatin regulation may be helpful for achieving correct cell reprogramming without inducing tumor formation and for developing new drugs for cancer treatment. This review focuses on the risk of tumor formation by human pluripotent stem cells, and on the possible treatment options if it occurs. Potential new techniques that target epigenetic processes and chromatin regulation provide opportunities for human cancer modeling and clinical applications of regenerative medicine.
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Affiliation(s)
- Kenly Wuputra
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Ying-Chu Lin
- School of Dentistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Shigeo Saito
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
- Saito Laboratory of Cell Technology Institute, Yaita, Tochigi, 329-1571, Japan.
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan.
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
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Wu X, Liu M, Zhu H, Wang J, Dai W, Li J, Zhu D, Tang W, Xiao Y, Lin J, Zhang W, Sun Y, Zhang Y, Chen Y, Li G, Li A, Xiang L, Liu S, Wang J. Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:277. [PMID: 31234902 PMCID: PMC6591922 DOI: 10.1186/s13046-019-1270-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 06/05/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND The deubiquitinating enzyme ubiquitin-specific protease 3 (USP3) plays a crucial role in numerous biological processes. The aberrant expression of USP3 may have an important role in tumor development. However, the mechanism by which USP3 promotes gastric cancer (GC) metastasis remains largely unknown. METHODS Effects of USP3 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated utilizing proteomics, RT-PCR, western blotting, immunohistochemistry, immunofluorescence, cell invasion and migration assays and xenograft tumor models. RESULTS USP3 expression was upregulated in GC compared with matched normal tissues and was predictive of poor survival. USP3 also promoted migration and epithelial-to-mesenchymal transition (EMT) in GC cells. Moreover, TGF-β1 induced USP3 expression, and USP3 knockdown inhibited TGF-β1-induced EMT. Furthermore, we utilized Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in USP3-overexpressing cells compared with control cells. Importantly, we found that SUZ12 is indispensable for USP3-mediated oncogenic activity in GC. We observed that USP3 interacted with and stabilized SUZ12 via deubiquitination. SUZ12 knockdown inhibited USP3-induced migration and invasion, as well as EMT in GC cells. Examination of clinical samples confirmed that USP3 expression was positively correlated with SUZ12 protein expression and that the levels of USP3 or SUZ12 protein were negatively correlated with the levels of E-cadherin protein. CONCLUSIONS These findings identify USP3 as a critical regulator. The USP3-SUZ12 axis might promote tumor progression and could be a potential therapeutic candidate for human GC.
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Affiliation(s)
- Xiaosheng Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Mengwei Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Huiqiong Zhu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jing Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Weiyu Dai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiaying Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Danping Zhu
- Department of Clinical Laboratory, General Hospital of Southern Theatre Command, Guangzhou, 510010, China
| | - Weimei Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yizhi Xiao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jianjiao Lin
- Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China
| | - Wenjing Zhang
- Department of Medical Oncology, the First people's Hospital of Yunnan Province, Medical School of Kunming University of Science and Technology, Kunming, 650032, China
| | - Yong Sun
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yi Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yaying Chen
- Department of Gastroenterology, The third affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Xiang
- Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China. .,Department of Digestive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. .,Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China. .,Department of Digestive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Jide Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. .,Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China. .,Department of Digestive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
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7
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Abstract
Multiple studies focused on tumor heterogeneity and cellular hierarchies have demonstrated the role of cancer stem cells (CSC) in tumor initiation and recurrence. Colorectal cancer is one of the leading causes of cancer-related death and is hierarchically organized, with the majority of tumor cells descending from a small population of colon cancer stem cells (CCSCs). Such a rare self-renewing population is marked by the acquisition of distinct chromatin regulation and transcriptional programs. Fundamental molecular deviations between CCSCs and bulk tumor cells as well as normal tissues represent a unique therapeutic access to develop novel, selective anticancer therapies.In this chapter, we describe a methodological pipeline to identify novel molecules to selectively target human CCSC. We present a point-by-point description of a typical phenotypic molecular screening experiment, aiming to identify selective modulators of human CCSCs vs. normal intestinal progenitor cells.
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Affiliation(s)
- Yannick D Benoit
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
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Shi Y, Xu L, Tao M, Fang L, Lu J, Gu H, Ma S, Lin T, Wang Y, Bao W, Qiu A, Zhuang S, Liu N. Blockade of enhancer of zeste homolog 2 alleviates renal injury associated with hyperuricemia. Am J Physiol Renal Physiol 2018; 316:F488-F505. [PMID: 30566000 DOI: 10.1152/ajprenal.00234.2018] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Hyperuricemia has been identified as an independent risk factor for chronic kidney disease (CKD) and is associated with the progression of kidney diseases. It remains unknown whether enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, can regulate metabolism of serum uric acid and progression of renal injury induced by hyperuricemia. In this study, we demonstrated that blockade of EZH2 with 3-DZNeP, a selective EZH2 inhibitor, or silencing of EZH2 with siRNA inhibited uric acid-induced renal fibroblast activation and phosphorylation of Smad3, epidermal growth factor receptor (EGFR), and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in cultured renal fibroblasts. Inhibition of EZH2 also suppressed proliferation of renal fibroblasts and epithelial-mesenchymal transition of tubular cells. In a mouse model of renal injury induced by hyperuricemia, EZH2 and trimethylation of histone H3 at lysine27 expression levels were enhanced, which was coincident with renal damage and increased expression of lipocalin-2 and cleaved caspase-3. Inhibition of EZH2 with 3-DZNeP blocked all these responses. Furthermore, 3-DZNeP treatment decreased the level of serum uric acid and xanthine oxidase activity, alleviated renal interstitial fibrosis, inhibited activation of transforming growth factor-β/Smad3, EGFR/ERK1/2, and nuclear factor-κB signaling pathways, as well as reduced expression of multiple chemokines/cytokines. Collectively, EZH2 inhibition can reduce the level of serum uric acid and alleviate renal injury and fibrosis through a mechanism associated with inhibition of multiple signaling pathways. Targeting EZH2 may be a novel strategy for the treatment of hyperuricemia-induced CKD.
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Affiliation(s)
- Yingfeng Shi
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Liuqing Xu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Min Tao
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Lu Fang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Jiasun Lu
- Department of Urology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Hongwei Gu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Shuchen Ma
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Tao Lin
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Yi Wang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Wenfang Bao
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Andong Qiu
- School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University , Shanghai , China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.,Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University , Providence, Rhode Island
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
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Genadry KC, Pietrobono S, Rota R, Linardic CM. Soft Tissue Sarcoma Cancer Stem Cells: An Overview. Front Oncol 2018; 8:475. [PMID: 30416982 PMCID: PMC6212576 DOI: 10.3389/fonc.2018.00475] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 10/05/2018] [Indexed: 12/18/2022] Open
Abstract
Soft tissue sarcomas (STSs) are an uncommon group of solid tumors that can arise throughout the human lifespan. Despite their commonality as non-bony cancers that develop from mesenchymal cell precursors, they are heterogeneous in their genetic profiles, histology, and clinical features. This has made it difficult to identify a single target or therapy specific to STSs. And while there is no one cell of origin ascribed to all STSs, the cancer stem cell (CSC) principle—that a subpopulation of tumor cells possesses stem cell-like properties underlying tumor initiation, therapeutic resistance, disease recurrence, and metastasis—predicts that ultimately it should be possible to identify a feature common to all STSs that could function as a therapeutic Achilles' heel. Here we review the published evidence for CSCs in each of the most common STSs, then focus on the methods used to study CSCs, the developmental signaling pathways usurped by CSCs, and the epigenetic alterations critical for CSC identity that may be useful for further study of STS biology. We conclude with discussion of some challenges to the field and future directions.
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Affiliation(s)
- Katia C Genadry
- Division of Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
| | - Silvia Pietrobono
- Department of Hematology-Oncology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
| | - Rossella Rota
- Department of Hematology-Oncology, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
| | - Corinne M Linardic
- Division of Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.,Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, United States
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10
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Wu Q, Chen Z, Zhang G, Zhou W, Peng Y, Liu R, Chen C, Feng J. EZH2 induces the expression of miR-1301 as a negative feedback control mechanism in triple negative breast cancer. Acta Biochim Biophys Sin (Shanghai) 2018; 50:693-700. [PMID: 29790898 DOI: 10.1093/abbs/gmy050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 04/17/2018] [Indexed: 12/25/2022] Open
Abstract
Breast cancer is one of the most common malignancies in women. ERα, PR, and HER2 triple negative breast cancer (TNBC) is the current research focus because of the lack of effective targeted therapies. In our study, lentivirus systems were used to overexpress EZH2 and miR-1301 in TNBC cell lines. Western blot analysis and RT-qPCR were used to detect the protein and microRNA levels. The TCGA and Kaplan Meier plotter databases were used to analyze the EZH2 and miR-1301 expression levels in breast cancer. The effect of miR-1301 overexpression on cell proliferation, migration and colony formation were determined by using the sulforhodamine B (SRB) assay, wound healing assay and colony formation assay, respectively. Furthermore, an xenograft mouse model was used to investigate the function of miR-1301 overexpression in vivo. Finally, dual luciferase reporter assay was used to verify the binding site of EZH2 and miR-1301. We found that EZH2 induced the expression of miR-1301 in two TNBC cell lines, HCC1937 and HCC1806. Overexpression of miR-1301 suppressed TNBC cell proliferation, migration and colony formation, as well as the xenograft tumor growth in immunodeficient mice. Interestingly, miR-1301 inhibited the expression of EZH2 by binding to the 3'-UTR of EZH2 gene. These data suggest that EZH2 induces the expression of miR-1301 as a negative feedback control mechanism in TNBC.
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Affiliation(s)
- Qiuju Wu
- Fengxian District Center Hospital Graduate Student Training Base, Jinzhou Medical University, Shanghai, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- Department of Laboratory Medicine, Fengxian District Center Hospital, Shanghai, China
| | - Zekun Chen
- Department of Laboratory Medicine, Huizhou No. 3 People's Hospital, Affiliated hospital of Guangzhou Medical University, Huizhou, China
| | - Guihua Zhang
- Department of Laboratory Medicine, Huizhou No. 3 People's Hospital, Affiliated hospital of Guangzhou Medical University, Huizhou, China
| | - Wenhui Zhou
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - You Peng
- Department of Laboratory Medicine, Fengxian District Center Hospital, Shanghai, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Jing Feng
- Department of Laboratory Medicine, Fengxian District Center Hospital, Shanghai, China
- Shanghai University of Medicine & Health Sciences Affiliated Six People's Hospital South Campus, Shanghai, China
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11
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Targeting PTEN in Colorectal Cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1110:55-73. [DOI: 10.1007/978-3-030-02771-1_5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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12
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Zhou J, Nie D, Li J, Du X, Lu Y, Li Y, Liu C, Dai W, Wang Y, Jin Y, Pan J. PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia. Clin Cancer Res 2017; 24:145-157. [PMID: 29070525 DOI: 10.1158/1078-0432.ccr-17-1533] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 09/21/2017] [Accepted: 10/18/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism.Experimental Design: Human primary CML CD34+ cells and retrovirally BCR-ABL-driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by GSK126- or EZH2-specific shRNA in vitro and in vivo Recruitment of EZH2 and H3K27me3 on the promoter of tumor-suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation assay.Results: Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown.Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. Clin Cancer Res; 24(1); 145-57. ©2017 AACR.
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Affiliation(s)
- Jingfeng Zhou
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Danian Nie
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Juan Li
- Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Du
- Department of Hematology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yuhong Lu
- Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Yangqiu Li
- Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Chang Liu
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Wei Dai
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Yun Wang
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Yanli Jin
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China.
| | - Jingxuan Pan
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China. .,State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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13
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Eun K, Ham SW, Kim H. Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep 2017; 50:117-125. [PMID: 27998397 PMCID: PMC5422023 DOI: 10.5483/bmbrep.2017.50.3.222] [Citation(s) in RCA: 251] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Indexed: 12/14/2022] Open
Abstract
Most of the cancers are still incurable human diseases. According to recent findings, especially targeting cancer stem cells (CSCs) is the most promising therapeutic strategy. CSCs take charge of a cancer hierarchy, harboring stem cell-like properties involving self-renewal and aberrant differentiation potential. Most of all, the presence of CSCs is closely associated with tumorigenesis and therapeutic resistance. Despite the numerous efforts to target CSCs, current anti-cancer therapies are still impeded by CSC-derived cancer malignancies; increased metastases, tumor recurrence, and even acquired resistance against the anti-CSC therapies developed in experimental models. One of the most forceful underlying reasons is a “cancer heterogeneity” due to “CSC plasticity” A comprehensive understanding of CSC-derived heterogeneity will provide novel insights into the establishment of efficient targeting strategies to eliminate CSCs. Here, we introduce findings on mechanisms of CSC reprogramming and CSC plasticity, which give rise to phenotypically varied CSCs. Also, we suggest concepts to improve CSC-targeted therapy in order to overcome therapeutic resistance caused by CSC plasticity and heterogeneity.
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Affiliation(s)
- Kiyoung Eun
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
| | - Seok Won Ham
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
| | - Hyunggee Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
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14
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Huang T, Lin C, Zhong LLD, Zhao L, Zhang G, Lu A, Wu J, Bian Z. Targeting histone methylation for colorectal cancer. Therap Adv Gastroenterol 2017; 10:114-131. [PMID: 28286564 PMCID: PMC5330608 DOI: 10.1177/1756283x16671287] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
As a leading cause of cancer deaths worldwide, colorectal cancer (CRC) results from accumulation of both genetic and epigenetic alterations. Disruption of epigenetic regulation in CRC, particularly aberrant histone methylation mediated by histone methyltransferases (HMTs) and demethylases (HDMs), have drawn increasing interest in recent years. In this paper, we aim to review the roles of histone methylation and associated enzymes in the pathogenesis of CRC, and the development of small-molecule modulators to regulate histone methylation for treating CRC. Multiple levels of evidence suggest that aberrant histone methylations play important roles in CRC. More than 20 histone-methylation enzymes are found to be clinically relevant to CRC, including 17 oncoproteins and 8 tumor suppressors. Inhibitors of EZH2 and DOT1L have demonstrated promising therapeutic effects in preclinical CRC treatment. Potent and selective chemical probes of histone-methylation enzymes are required for validation of their functional roles in carcinogenesis and clinical translations as CRC therapies. With EZH2 inhibitor EPZ-6438 entering into phase I/II trials for advanced solid tumors, histone methylation is emerging as a promising target for CRC.
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Affiliation(s)
- Tao Huang
- Lab of Brain–Gut Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, PR China
| | - Chengyuan Lin
- Lab of Brain–Gut Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, PR China YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming, PR China
| | - Linda L. D. Zhong
- Lab of Brain–Gut Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, PR China
| | - Ling Zhao
- Lab of Brain–Gut Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, PR China
| | - Ge Zhang
- Lab of Brain–Gut Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, PR China
| | - Aiping Lu
- Lab of Brain–Gut Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, PR China
| | - Jiang Wu
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, PR China
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15
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Mutlu M, Saatci Ö, Ansari SA, Yurdusev E, Shehwana H, Konu Ö, Raza U, Şahin Ö. miR-564 acts as a dual inhibitor of PI3K and MAPK signaling networks and inhibits proliferation and invasion in breast cancer. Sci Rep 2016; 6:32541. [PMID: 27600857 PMCID: PMC5013276 DOI: 10.1038/srep32541] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 08/11/2016] [Indexed: 12/19/2022] Open
Abstract
Dysregulation of PI3K and MAPK pathways promotes uncontrolled cell proliferation, apoptotic inhibition and metastasis. Individual targeting of these pathways using kinase inhibitors has largely been insufficient due to the existence of cross-talks between these parallel cascades. MicroRNAs are small non-coding RNAs targeting several genes simultaneously and controlling cancer-related processes. To identify miRNAs repressing both PI3K and MAPK pathways in breast cancer, we re-analyzed our previous miRNA mimic screen data with reverse phase protein array (RPPA) output, and identified miR-564 inhibiting both PI3K and MAPK pathways causing markedly decreased cell proliferation through G1 arrest. Moreover, ectopic expression of miR-564 blocks epithelial-mesenchymal transition (EMT) and reduces migration and invasion of aggressive breast cancer cells. Mechanistically, miR-564 directly targets a network of genes comprising AKT2, GNA12, GYS1 and SRF, thereby facilitating simultaneous repression of PI3K and MAPK pathways. Notably, combinatorial knockdown of these target genes using a cocktail of siRNAs mimics the phenotypes exerted upon miR-564 expression. Importantly, high miR-564 expression or low expression of target genes in combination is significantly correlated with better distant relapse-free survival of patients. Overall, miR-564 is a potential dual inhibitor of PI3K and MAPK pathways, and may be an attractive target and prognostic marker for breast cancer.
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Affiliation(s)
- Merve Mutlu
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Özge Saatci
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Suhail A Ansari
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Emre Yurdusev
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Huma Shehwana
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Özlen Konu
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Umar Raza
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Özgür Şahin
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
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16
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McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Yang LV, Montalto G, Cervello M, Libra M, Nicoletti F, Scalisi A, Torino F, Fenga C, Neri LM, Marmiroli S, Cocco L, Martelli AM. Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:2942-2976. [PMID: 27612668 DOI: 10.1016/j.bbamcr.2016.09.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/14/2016] [Accepted: 09/02/2016] [Indexed: 02/07/2023]
Abstract
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA.
| | - Dariusz Rakus
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Agnieszka Gizak
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Steve L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, USA
| | - Timothy L Fitzgerald
- Department of Surgery, Brody School of Medicine at East Carolina University, USA
| | - Li V Yang
- Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, USA
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Massimo Libra
- Department of Bio-medical Sciences, University of Catania, Catania, Italy
| | | | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP-Catania, Catania 95100, Italy
| | - Francesco Torino
- Department of Systems Medicine, Chair of Medical Oncology, Tor Vergata University of Rome, Rome, Italy
| | - Concettina Fenga
- Department of Biomedical, Odontoiatric, Morphological and Functional Images, Occupational Medicine Section - Policlinico "G. Martino" - University of Messina, Messina 98125, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Sandra Marmiroli
- Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
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17
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Abdalkader L, Oka T, Takata K, Sato H, Murakami I, Otte AP, Yoshino T. Aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms. Pathology 2016; 48:467-82. [PMID: 27311868 DOI: 10.1016/j.pathol.2016.05.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 05/03/2016] [Accepted: 05/04/2016] [Indexed: 11/25/2022]
Abstract
The Polycomb repressive complex-2 members (EZH2, EED, SUZ12 and EZH1) are important regulators of haematopoiesis, cell cycle and differentiation. Over-expression of EZH2 has been linked to cancer metastases and poor prognosis. Detailed information on the expression of other members in normal and neoplastic lymphoid tissue remains to be elucidated. Immunohistochemical and immunofluorescent analyses of 156 samples from haematopoietic neoplasms patients and 27 haematopoietic cell lines were used. B-cell neoplasms showed a significant over-expression of EZH2, EED and SUZ12 in the aggressive subtypes compared to the indolent subtypes and normal tissue (p = 0.000-0.046) while expression of EZH1 was decreased in mantle cell lymphoma compared to normal tissue (p = 0.011). T/NK-cell neoplasms also showed significant over-expression of EZH2, EED and SUZ12 (p = 0.000-0.002) and decreased expression of EZH1 (p = 0.001) compared to normal cells. EZH2 and EZH1 have opposite expression patterns both in normal and neoplastic lymphoid tissues as well as an opposite relation to Ki-67. These results were supported by western blotting analyses. Immunofluorescent staining revealed a difference in the intracellular localisation of EZH1 compared to other members. These evidences suggest that EZH2 and EZH1 are important in the counter-balancing mechanisms controlling proliferation/resting of lymphoid cells. The disruption of the balanced EZH2/EZH1 ratio may play important roles in the pathogenesis of lymphomas.
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Affiliation(s)
- Lamia Abdalkader
- Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Department of Pathology, Faculty of Medicine, Mansoura University, Egypt
| | - Takashi Oka
- Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
| | - Katsuyoshi Takata
- Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hiaki Sato
- Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, Japan
| | - Ichiro Murakami
- Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Department of Molecular Pathology, Tottori University Medical School, Japan
| | - Arie P Otte
- Department of Biochemistry Swammerdam Institute for Life Sciences, University of Amsterdam, Netherlands
| | - Tadashi Yoshino
- Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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18
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Mechanistic insight into the aberrant silencing of the keratin 13 gene in oral squamous cell carcinoma cells. J Oral Biosci 2016. [DOI: 10.1016/j.job.2016.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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19
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Roostaee A, Benoit YD, Boudjadi S, Beaulieu JF. Epigenetics in Intestinal Epithelial Cell Renewal. J Cell Physiol 2016; 231:2361-7. [PMID: 27061836 PMCID: PMC5074234 DOI: 10.1002/jcp.25401] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 04/05/2016] [Indexed: 12/15/2022]
Abstract
A controlled balance between cell proliferation and differentiation is essential to maintain normal intestinal tissue renewal and physiology. Such regulation is powered by several intracellular pathways that are translated into the establishment of specific transcription programs, which influence intestinal cell fate along the crypt-villus axis. One important check-point in this process occurs in the transit amplifying zone of the intestinal crypts where different signaling pathways and transcription factors cooperate to manage cellular proliferation and differentiation, before secretory or absorptive cell lineage terminal differentiation. However, the importance of epigenetic modifications such as histone methylation and acetylation in the regulation of these processes is still incompletely understood. There have been recent advances in identifying the impact of histone modifications and chromatin remodelers on the proliferation and differentiation of normal intestinal crypt cells. In this review we discuss recent discoveries on the role of the cellular epigenome in intestinal cell fate, development, and tissue renewal. J. Cell. Physiol. 231: 2361-2367, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
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Affiliation(s)
- Alireza Roostaee
- Faculty of Medicine and Health Sciences, Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Yannick D Benoit
- Faculty of Health Sciences, McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Salah Boudjadi
- Faculty of Medicine and Health Sciences, Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Jean-François Beaulieu
- Faculty of Medicine and Health Sciences, Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
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20
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Chen H, Gao S, Li J, Liu D, Sheng C, Yao C, Jiang W, Wu J, Chen S, Huang W. Wedelolactone disrupts the interaction of EZH2-EED complex and inhibits PRC2-dependent cancer. Oncotarget 2016; 6:13049-59. [PMID: 25944687 PMCID: PMC4536998 DOI: 10.18632/oncotarget.3790] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/18/2015] [Indexed: 01/02/2023] Open
Abstract
Polycomb repressive complex 2 (PRC2), which is responsible for the trimethylation of H3K27 (H3K27me3), plays a part in tumorigenesis, development and/or maintenance of adult tissue specificity. The pivotal role of PRC2 in cancer makes it a therapeutic target for epigenetic cancer therapy. However, natural compounds targeting the enhancer of zeste homolog 2 (EZH2) - embryonic ectoderm development (EED) interaction to disable PRC2 complex are scarcely reported. Here, we reported the screening and identification of natural compounds which could disrupt the EZH2-EED interaction. One of these compounds, wedelolactone, binds to EED with a high affinity (KD = 2.82 μM), blocks the EZH2-EED interaction in vitro, induces the degradation of PRC2 core components and modulates the expression of detected PRC2 downstream targets and cancer-related genes. Furthermore, some PRC2-dependent cancer cells undergone growth arrest upon treatment with wedelolactone. Thus, wedelolactone and its derivatives which target the EZH2-EED interaction could be candidates for the treatment of PRC2-dependent cancer.
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Affiliation(s)
- Huiming Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.,School of Life Sciences, Anhui University, Hefei 230039, China
| | - Shijuan Gao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiandong Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Dong Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Chunjie Sheng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Chen Yao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.,School of Life Sciences, Anhui University, Hefei 230039, China
| | - Wei Jiang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiaoxiang Wu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.,School of Life Sciences, Anhui University, Hefei 230039, China
| | - Shuai Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wenlin Huang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,The Key Laboratory of Tumor Targeted Medicine in Guangdong Province, Guangzhou Double Bio-product Inc., Guangzhou 510663, China
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21
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Minton DR, Fu L, Mongan NP, Shevchuk MM, Nanus DM, Gudas LJ. Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma. Clin Cancer Res 2016; 22:2791-801. [PMID: 26783287 DOI: 10.1158/1078-0432.ccr-15-1511] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 01/07/2016] [Indexed: 12/12/2022]
Abstract
PURPOSE We delineated the functions of the hypoxia-inducible factor-1α (HIF1α) target NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) in clear cell renal cell carcinoma (ccRCC) and characterized NDUFA4L2 as a novel molecular target for ccRCC treatment. EXPERIMENTAL DESIGN We evaluated normal kidney and ccRCC patient microarray and RNAseq data from Oncomine and The Cancer Genome Atlas for NDUFA4L2 mRNA levels and the clinical implications of high NDUFA4L2 expression. In addition, we examined normal kidney and ccRCC patient tissue samples, human ccRCC cell lines, and murine models of ccRCC for NDUFA4L2 mRNA and protein expression. Utilizing short hairpin RNA, we performed NDUFA4L2 knockdown experiments and analyzed the proliferation, clonogenicity, metabolite levels, cell structure, and autophagy in ccRCC cell lines in culture. RESULTS We found that NDUFA4L2 mRNA and protein are highly expressed in ccRCC samples but undetectable in normal kidney tissue samples, and that NDUFA4L2 mRNA expression correlates with tumor stage and lower overall survival. In addition, we demonstrated that NDUFA4L2 is an HIF1α target in ccRCC and that NDUFA4L2 knockdown has a profound antiproliferative effect, alters metabolic pathways, and causes major stress in cultured RCC cells. CONCLUSIONS Collectively, our data show that NDUFA4L2 is a novel molecular target for ccRCC treatment. Clin Cancer Res; 22(11); 2791-801. ©2016 AACR.
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Affiliation(s)
- Denise R Minton
- Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York. Weill Cornell Graduate School of Medical Sciences-Pharmacology Program, WCMC, New York, New York. Department of Pathology, New York University (NYU) School of Medicine, New York, New York
| | - Leiping Fu
- Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York
| | - Nigel P Mongan
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, The University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom
| | - Maria M Shevchuk
- Department of Pathology and Laboratory Medicine, WCMC of Cornell University, New York, New York. Meyer Cancer Center, WCMC of Cornell University, New York, New York
| | - David M Nanus
- Meyer Cancer Center, WCMC of Cornell University, New York, New York. Division of Hematology and Medical Oncology of the Department of Medicine, WCMC of Cornell University, New York, New York
| | - Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York. Meyer Cancer Center, WCMC of Cornell University, New York, New York.
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22
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Zhou X, Zang X, Ponnusamy M, Masucci MV, Tolbert E, Gong R, Zhao TC, Liu N, Bayliss G, Dworkin LD, Zhuang S. Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression. J Am Soc Nephrol 2015; 27:2092-108. [PMID: 26701983 DOI: 10.1681/asn.2015040457] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 10/30/2015] [Indexed: 01/06/2023] Open
Abstract
Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. However, the role of EZH2 in renal fibrogenesis remains unexplored. In this study, we found high expression of EZH2 and H3K27me3 in cultured renal fibroblasts and fibrotic kidneys from mice with unilateral ureteral obstruction and humans with CKD. Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) or GSK126 or siRNA-mediated silencing of EZH2 inhibited serum- and TGFβ1-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of α-smooth muscle actin in the obstructed kidney. Injury to the kidney enhanced Smad7 degradation, Smad3 phosphorylation, and TGFβ receptor 1 expression, and 3-DZNeP administration prevented these effects. 3-DZNeP also suppressed phosphorylation of the renal EGF and PDGFβ receptors and downstream signaling molecules signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 after injury. Moreover, EZH2 inhibition increased the expression of phosphatase and tensin homolog (PTEN), a protein previously associated with dephosphorylation of tyrosine kinase receptors in the injured kidney and serum-stimulated renal interstitial fibroblasts. Finally, blocking PTEN with SF1670 largely diminished the inhibitory effect of 3-DZNeP on renal myofibroblast activation. These results uncovered the important role of EZH2 in mediating the development of renal fibrosis by downregulating expression of Smad7 and PTEN, thus activating profibrotic signaling pathways. Targeted inhibition of EZH2, therefore, could be a novel therapy for treating CKD.
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Affiliation(s)
- Xiaoxu Zhou
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island; Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiujuan Zang
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island; Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, China
| | - Murugavel Ponnusamy
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
| | - Monica V Masucci
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
| | - Evelyn Tolbert
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
| | - Rujun Gong
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
| | - Ting C Zhao
- Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, Providence, Rhode Island; and
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - George Bayliss
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
| | - Lance D Dworkin
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
| | - Shougang Zhuang
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells 2015; 7:1150-1184. [PMID: 26516408 PMCID: PMC4620423 DOI: 10.4252/wjsc.v7.i9.1150] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/30/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
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Katona BW, Liu Y, Ma A, Jin J, Hua X. EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells. Cancer Biol Ther 2015; 15:1677-87. [PMID: 25535899 DOI: 10.4161/15384047.2014.972776] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Metastatic colon cancer has a 5-year survival of less than 10% despite the use of aggressive chemotherapeutic regimens. As signaling from epidermal growth factor receptor (EGFR) is often enhanced and epigenetic regulation is often altered in colon cancer, it is desirable to enhance the efficacy of EGFR-directed therapy by co-targeting an epigenetic pathway. We showed that the histone methyltransferase EZH2, which catalyzes methylation of histone H3 lysine 27 (H3K27), was upregulated in colon cancers in The Cancer Genome Atlas (TCGA) database. Since co-inhibition of both EGFR and EZH2 has not been studied in colon cancer, we examined the effects of co-inhibition of EGFR and EZH2 on 2 colon cancer cell lines, HT-29 and HCT-15. Co-inhibition of EZH2 and EGFR with the small molecules UNC1999 and gefitinib, led to a significant decrease in cell number and increased apoptosis compared to inhibition of either pathway alone, and similar results were noted after EZH2 shRNA knockdown. Moreover, co-inhibition of EZH2 and EGFR also significantly induced autophagy, indicating that autophagy may play a role in the observed synergy. Together, these findings suggest that inhibition of both EZH2 and EGFR serves as an effective method to increase the efficacy of EGFR inhibitors in suppressing colon cancer cells.
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Affiliation(s)
- Bryson W Katona
- a Division of Gastroenterology; University of Pennsylvania Perelman School of Medicine ; Philadelphia , PA USA
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25
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Abstract
Post-translational modifications of histones (so-called epigenetic modifications) play a major role in transcriptional control and normal development, and are tightly regulated. Disruption of their control is a frequent event in disease. In particular, the methylation of lysine 27 on histone H3 (H3K27), induced by the methylase EZH2, emerges as a key control of gene expression and a major regulator of cell physiology. The identification of driver mutations in EZH2 has already led to new prognostic and therapeutic advances, and new classes of potent and specific inhibitors for EZH2 show promising results in preclinical trials. This review examines the roles of histone lysine methylases and demethylases in cells and focuses on the recent knowledge and developments about EZH2.
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Sha M, Mao G, Wang G, Chen Y, Wu X, Wang Z. DZNep inhibits the proliferation of colon cancer HCT116 cells by inducing senescence and apoptosis. Acta Pharm Sin B 2015; 5:188-93. [PMID: 26579445 PMCID: PMC4629229 DOI: 10.1016/j.apsb.2015.01.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 12/30/2014] [Accepted: 01/27/2015] [Indexed: 12/31/2022] Open
Abstract
EZH2 is over-expressed in human colon cancer and is closely associated with tumor proliferation, metastasis and poor prognosis. Targeting and inhibiting EZH2 may be an effective therapeutic strategy for colon cancer. 3-Deazaneplanocin A (DZNep), as an EZH2 inhibitor, can suppress cancer cell growth. However, the anti-cancer role of DZNep in colon cancer cells has been rarely studied. In this study, we demonstrate that DZNep can inhibit the growth and survival of colon cancer HCT116 cells by inducing cellular senescence and apoptosis. The study provides a novel view of anti-cancer mechanisms of DZNep in human colon cancer cells.
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Down-regulation of miR-489 contributes into NSCLC cell invasion through targeting SUZ12. Tumour Biol 2015; 36:6497-505. [DOI: 10.1007/s13277-015-3340-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 03/15/2015] [Indexed: 12/23/2022] Open
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Li Z, Wang Y, Qiu J, Li Q, Yuan C, Zhang W, Wang D, Ye J, Jiang H, Yang J, Cheng J. The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer. Oncotarget 2014; 4:2532-49. [PMID: 24345883 PMCID: PMC3926847 DOI: 10.18632/oncotarget.1503] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer.
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Affiliation(s)
- Zhongwu Li
- Head Neck Cancer Center, Institute of Stomatology, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China PRC
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29
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Abstract
The cancer stem cell (CSC) hypothesis postulates that there is a hierarchy of cellular differentiation within cancers and that the bulk population of tumor cells is derived from a relatively small population of multi-potent neoplastic stem-like cells (CSCs). This tumor-initiating cell population plays an important role in maintaining tumor growth through their unlimited self-renewal, therapeutic resistance, and capacity to propagate tumors through asymmetric cell division. Recent findings from multiple laboratories show that cancer progenitor cells have the capacity to de-differentiate and acquire a stem-like phenotype in response to either genetic manipulation or environmental cues. These findings suggest that CSCs and relatively differentiated progenitors coexist in dynamic equilibrium and are subject to bidirectional conversion. In this review, we discuss emerging concepts regarding the stem-like phenotype, its acquisition by cancer progenitor cells, and the molecular mechanisms involved. Understanding the dynamic equilibrium between CSCs and cancer progenitor cells is critical for the development of novel therapeutic strategies that focus on depleting tumors of their tumor-propagating cell population.
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Affiliation(s)
| | - Yunqing Li
- Hugo W. Moser Research Institute at Kennedy Krieger, USA; Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - John Laterra
- Hugo W. Moser Research Institute at Kennedy Krieger, USA; Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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30
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Benard A, Goossens-Beumer IJ, van Hoesel AQ, Horati H, Putter H, Zeestraten ECM, van de Velde CJH, Kuppen PJK. Prognostic value of polycomb proteins EZH2, BMI1 and SUZ12 and histone modification H3K27me3 in colorectal cancer. PLoS One 2014; 9:e108265. [PMID: 25243792 PMCID: PMC4171510 DOI: 10.1371/journal.pone.0108265] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/20/2014] [Indexed: 02/07/2023] Open
Abstract
Numerous changes in epigenetic mechanisms have been described in various types of tumors. In search for new biomarkers, we investigated the expression of Polycomb-group (PcG) proteins EZH2, BMI1 and SUZ12 and associated histone modification H3K27me3 in colorectal cancer. Nuclear expression of PcG proteins and histone modification H3K27me3 were immunohistochemically (IHC) stained on a tissue microarray (TMA), including 247 tumor tissues and 47 normal tissues, and scored using the semi-automated Ariol system. Tumor tissues showed higher expression of EZH2 (p = 0.05) and H3K27me3 (p<0.001) as compared to their normal counterparts. Combined marker trend analyses indicated that an increase in the number of markers showing high expression was associated with better prognosis. High expression of all four markers in the combined marker analyses was correlated with the best patient survival and the longest recurrence-free survival, with overall survival (p = 0.01, HR 0.42(0.21-0.84)), disease-free survival (p = 0.007, HR 0.23(0.08-0.67) and local recurrence-free survival (p = 0.02, HR 0.30(0.11-0.84)). In conclusion, we found that expression of PcG proteins and H3K27me3 showed prognostic value in our study cohort. Better stratification of patients was obtained by combining the expression data of the investigated biomarkers as compared to the individual markers, underlining the importance of investigating multiple markers simultaneously.
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Affiliation(s)
- Anne Benard
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- * E-mail:
| | | | - Anneke Q. van Hoesel
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Hamed Horati
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Hein Putter
- Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
| | | | | | - Peter J. K. Kuppen
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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31
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Dong P, Konno Y, Watari H, Hosaka M, Noguchi M, Sakuragi N. The impact of microRNA-mediated PI3K/AKT signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer. J Transl Med 2014; 12:231. [PMID: 25141911 PMCID: PMC4145234 DOI: 10.1186/s12967-014-0231-0] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Accepted: 08/12/2014] [Indexed: 02/06/2023] Open
Abstract
Activation of the PI3K/AKT pathway, a common mechanism in all subtypes of endometrial cancers (endometrioid and non-endometrioid tumors), has important roles in contributing to epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) features. MicroRNAs (miRNAs) are small non-coding RNA molecules that concurrently affect multiple target genes, and regulate a wide range of genes involved in modulating EMT and CSC properties. Here we overview the recent advances revealing the impact of miRNAs on EMT and CSC phenotypes in tumors including endometrial cancer via regulating PI3K/AKT pathway. MiRNAs are crucial mediators of EMT and CSC through targeting PTEN-PI3K-AKT-mTOR axis. In endometrial cancer cells, miRNAs can activate or attenuate EMT and CSC by targeting PTEN and other EMT-associated genes, such as Twist1, ZEB1 and BMI-1. More detailed studies of miRNAs will deepen our understanding of the molecular basis underlying PI3K/AKT-induced endometrial cancer initiation and progression. Targeting key signaling components of PI3K/AKT pathway by restoring or inhibiting miRNA function holds promise as a potential therapeutic approach to suppress EMT and CSC in endometrial cancer.
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Affiliation(s)
- Peixin Dong
- Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
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32
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Benoit YD, Guezguez B, Boyd AL, Bhatia M. Molecular pathways: epigenetic modulation of Wnt-glycogen synthase kinase-3 signaling to target human cancer stem cells. Clin Cancer Res 2014; 20:5372-8. [PMID: 25006223 DOI: 10.1158/1078-0432.ccr-13-2491] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aberrant regulation of the canonical Wnt signaling pathway (Wnt-β-catenin-GSK3 axis) has been a prevalent theme in cancer biology since earlier observations until recent genetic discoveries gleaned from tumor genome sequencing. During the last few decades, a large body of work demonstrated the involvement of the Wnt-β-catenin-GSK3 signaling axis in the formation and maintenance of cancer stem cells (CSC) responsible for tumor growth in several types of human malignancies. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment on how embryonic and normal tissue stem cells are dysregulated in cancer to give rise to CSCs, and how canonical Wnt signaling might be involved. Here, we review emerging concepts highlighting the critical role of epigenetics in CSC development through abnormal canonical Wnt signaling. Finally, we refer to the characterization of novel and powerful inhibitors of chromatin organization machinery that, in turn, restore the Wnt-β-catenin-GSK3 signaling axis in malignant cells, and describe attempts/relevance to bring these compounds into preclinical and clinical studies.
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Affiliation(s)
- Yannick D Benoit
- Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Borhane Guezguez
- Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Allison L Boyd
- Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada
| | - Mickie Bhatia
- Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
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33
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Vaiopoulos AG, Athanasoula KC, Papavassiliou AG. Epigenetic modifications in colorectal cancer: Molecular insights and therapeutic challenges. Biochim Biophys Acta Mol Basis Dis 2014; 1842:971-980. [PMID: 24561654 DOI: 10.1016/j.bbadis.2014.02.006] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/12/2014] [Accepted: 02/15/2014] [Indexed: 12/11/2022]
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34
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Guezguez A, Paré F, Benoit YD, Basora N, Beaulieu JF. Modulation of stemness in a human normal intestinal epithelial crypt cell line by activation of the WNT signaling pathway. Exp Cell Res 2014; 322:355-364. [PMID: 24534551 DOI: 10.1016/j.yexcr.2014.02.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 02/04/2014] [Accepted: 02/07/2014] [Indexed: 12/21/2022]
Abstract
The small intestine consists of two histological compartments composed of the crypts and the villi. The function of the adult small intestinal epithelium is mediated by four different types of mature cells: enterocytes, goblet, enteroendocrine and Paneth. Undifferentiated cells reside in the crypts and produce these four types of mature cells. The niche-related Wnt and Bmp signaling pathways have been suggested to be involved in the regulation and maintenance of the stem cell microenvironment. In our laboratory, we isolated the first normal human intestinal epithelial crypt (HIEC) cell model from the human fetal intestine and in this study we investigated the expression of a panel of intestinal stem cell markers in HIEC cells under normal culture parameters as well as under conditions that mimic the stem cell microenvironment. The results showed that short term stimulation of HIEC cells with R-spondin 1 and Wnt-3a±SB-216763, a glycogen synthase kinase 3β (GSK3β) inhibitor, induced β-catenin/TCF activity and expression of the WNT target genes, cyclin D2 and LGR5. Treatment of HIEC cells with noggin, an antagonist of BMP signaling, abolished SMAD2/5/8 phosphorylation. Inducing a switch from inactive WNT/active BMP toward active WNT/inactive BMP pathways was sufficient to trigger a robust intestinal primordial stem-like cell signature with predominant LGR5, PHLDA1, PROM1, SMOC2 and OLFM4 expression. These findings demonstrate that even fully established cultures of intestinal cells can be prompted toward a CBC stem cell-like phenotype. This model should be useful for studying the regulation of human intestinal stem cell self-renewal and differentiation.
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Affiliation(s)
- Amel Guezguez
- Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
| | - Fréderic Paré
- Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
| | - Yannick D Benoit
- Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
| | - Nuria Basora
- Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
| | - Jean-François Beaulieu
- Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
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35
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Hemming S, Cakouros D, Gronthos S. Detachment of mesenchymal stem cells with trypsin/EDTA has no effect on apoptosis detection. Stem Cells 2014; 32:1991-2. [PMID: 24677681 DOI: 10.1002/stem.1710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 03/17/2014] [Indexed: 11/12/2022]
Affiliation(s)
- Sarah Hemming
- Mesechymal Stem Cell Laboratory, School of Health Sciences, Faculty of Health Sciences; Centre for Stem Cell Research, University of Adelaide, South Australia, Australia
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36
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Hui T, Wang C, Ye L. Comments on ethylenediaminetetraacetic acid contained in trypsin detaching cells for apoptosis detection. Stem Cells 2014; 32:1993-4. [PMID: 24677738 DOI: 10.1002/stem.1712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 01/16/2014] [Accepted: 01/18/2014] [Indexed: 02/05/2023]
Affiliation(s)
- Tianqian Hui
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
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Ciarapica R, Carcarino E, Adesso L, De Salvo M, Bracaglia G, Leoncini PP, Dall'agnese A, Verginelli F, Milano GM, Boldrini R, Inserra A, Stifani S, Screpanti I, Marquez VE, Valente S, Mai A, Puri PL, Locatelli F, Palacios D, Rota R. Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS. BMC Cancer 2014; 14:139. [PMID: 24575771 PMCID: PMC4016511 DOI: 10.1186/1471-2407-14-139] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 02/12/2014] [Indexed: 12/31/2022] Open
Abstract
Background Embryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts. Methods Embryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo. Results Here we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21Cip1. It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin, MCK and MHC. These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo. Conclusions These results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS.
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Affiliation(s)
- Roberta Ciarapica
- Department of Oncohematology, Laboratory of Angiogenesis, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S, Onofrio 4, 00165 Rome, Italy.
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Abstract
Epigenetics is "the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being" as defined by Conrad Waddington in 1942 in a discussion of the mechanisms of cell differentiation. More than seven decades later we know that these mechanisms include histone tail post-translational modifications, DNA methylation, ATP-dependent chromatin remodeling, and non-coding RNA pathways. Epigenetic modifications are powerful drugs targets, and combined targeting of multiple pathways is expected to significantly advance cancer therapy.
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