Overexpression of polycomb repressive complex 2 key components EZH2/SUZ12/EED as an unfavorable prognostic marker in cholangiocarcinoma

Wasenang, Wiphawan; Puapairoj, Anucha; Settasatian, Chatri; Proungvitaya, Siriporn; Limpaiboon, Temduang

doi:10.1016/j.prp.2019.152451

Cited by 16 publications

(9 citation statements)

References 36 publications

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“…There were 50% of Ov-CCA had high expression of EZH2, but the levels of expression did not correlate with patient prognosis. In contrast to our finding, high EZH2 expression was significantly associated with short overall survival in CCA ( Wasenang et al, 2019 ). Neither ARID1A expression nor mutation was correlated with EZH2 expression in our study.…”

Section: Discussioncontrasting

confidence: 99%

ARID1A alterations and their clinical significance in cholangiocarcinoma

Namjan

Techasen

Loilome

et al. 2020

PeerJ

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Background ARID1A is a member of the SWI/SNF chromatin remodeling complex. It functions as a tumor suppressor and several therapeutic targets in ARID1A-mutated cancers are currently under development, including EZH2. A synthetic lethal relationship between ARID1A and EZH2 has been revealed in several tumor entities. Although genomic alterations of ARID1A have been described in various cancers, no study has examined correlations between ARID1A gene mutation and protein expression with clinicopathologic parameters and prognosis, particularly in liver fluke-related cholangiocarcinoma (Ov-CCA). Here, we investigated the clinical significance of ARID1A mutations and protein expression in CCA tissues and determined whether there is a correlation with EZH2 protein expression. Methods We evaluated ARID1A and EZH2 immunoreactivity using immunohistochemistry in 98 Ov-CCA with a wide range of clinicopathological features. Somatic mutations of ARID1A were analyzed using the ICGC sequencing data in 489 of Ov and non Ov-CCA and assessed prognostic values. Results While detecting a loss or reduction of ARID1A expression in 54 cases (55%) in Ov-CCA, ARID1A expression was associated with ARID1A mutations (p < 0.001, adjusted p-value < 0.001). We observed that 12 of 13 tumors (92%) with loss of ARID1A expression had truncating mutations. There were nine of 13 tumors (69%) with loss of ARID1A expression and 25 of 41 tumors (61%) with low ARID1A expression exhibited distant metastasis (p = 0.028, adjusted p-value = 0.168). ARID1A was predominantly mutated in Ov-CCA compared to non Ov-CCA (24% and 14% in Ov-CCA and non Ov-CCA, respectively, p = 0.027). There were 36 of 72 (50%) and 52 of 79 (66%) tumors with ARID1A mutation showed tumor stage IV and T3/T4, respectively. The significant mutual exclusivity and co-occurrence between ARID1A and TP53/KRAS mutations were not found in ICGC cohort. In addition, high EZH2 expression, a potential synthetic lethal target in ARID1A-mutated tumors, was detected in 49 of 98 Ov-CCA (50%). Importantly, neither ARID1A expression nor ARID1A mutations correlated with EZH2 expression in this cohort. Conclusion We found that ARID1A inactivation, by somatic mutation or by loss of expression, frequently occurs in Ov-CCA. Reduction of ARID1A expression and/or somatic mutation was shown to be associated with CCA progression. These findings suggest that ARID1A may serve as a prognostic biomarker, and thus may be a promising therapeutic target for CCA.

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Section: Discussioncontrasting

confidence: 99%

ARID1A alterations and their clinical significance in cholangiocarcinoma

Namjan

Techasen

Loilome

et al. 2020

PeerJ

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“…Two recurrent mutation hot spots A682 and A692 were also identified in lymphoma patients (Bödör et al, 2013;Morin et al, 2011). In addition to EZH2 gain-offunction mutations, EZH2 overexpression seems to be prominent in carcinogenesis (Puppe et al, 2019;Sasaki et al, 2008;Wasenang et al, 2019). The first correlation between dysregulated EZH2 expression and cancer was reported by Varambally et al in the case of prostate cancer (Varambally et al, 2002).…”

Section: Year Number Of Publicationsmentioning

confidence: 93%

Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation

Pyziak

Sroka-Porada²,

Rzymski³

et al. 2021

Drug Development Research

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Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), is commonly overexpressed or mutated in many cancer types, both of hematological and solid nature. Till now, plenty of EZH2 small molecule inhibitors have been developed and some of them have already been tested in clinical trials. Most of these inhibitors, however, are effective only in limited cases in the context of EZH2 gain-of-function mutated tumors such as lymphomas. Other cancer types with aberrant EZH2 expression and function require alternative approaches for successful treatment. One possibility is to exploit synthetic lethal strategy, which is based on the phenomenon that concurrent loss of two genes is detrimental but the deletion of either of them leaves cell viable. In the context of EZH2/PRC2, the most promising synthetic lethal target seems to be SWItch/Sucrose Non-Fermentable chromatin remodeling complex (SWI/SNF), which is known to counteract PRC2 functions. SWI/SNF is heavily involved in carcinogenesis and its subunits have been found mutated in approximately 20% of tumors of different kinds. In the current review, we summarize the existing knowledge of synthetic lethal relationships between EZH2/PRC2 and components of the SWI/SNF complex and discuss in detail the potential application of existing EZH2 inhibitors in cancer patients harboring mutations in SWI/SNF proteins. We also highlight recent discoveries of EZH2 involvement in tumor microenvironment regulation and consequences for future therapies. Although clinical studies are limited, the fundamental research might help to understand which patients are most likely to benefit from therapies using EZH2 inhibitors.

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“…39,[43][44][45][46][47][48] Furthermore, abnormal expression of PRC2 components in the absence of mutations may lead to abnormal levels of H3K27me3, resulting in disrupted cell proliferation and differentiation in many cancers, including lung and liver. [49][50][51][52][53][54] Thus, increased expression of EZH2 is linked to promotion of proliferation, invasion, and metastasis through suppression of differentiation-linked Gata3 in triple-negative breast cancer. [55][56][57][58][59][60][61] In contrast, inhibition of EZH2 in cases where it is overexpressed rescues the proliferative phenotype and impedes malignant cell growth, as seen in breast and small-cell lung cancers.…”

Section: Polycomb Repressive Complex 2 and Cancermentioning

confidence: 99%

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

et al. 2021

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Genetic mutations or regulatory failures underlie cellular malfunction in many diseases, including colorectal cancer and inflammatory bowel diseases. However, mutational defects alone fail to explain the complexity of such disorders. Epigenetic regulation-control of gene action through chemical and structural changes of chromatin-provides a platform to integrate multiple extracellular inputs and prepares the cellular genome for appropriate gene expression responses. Coregulation by polycomb repressive complex 2-mediated trimethylation of lysine 27 on histone 3 and DNA methylation has emerged as one of the most influential epigenetic controls in colorectal cancer and many other diseases, but molecular details remain inadequate. Here we review the molecular interplay of these epigenetic features in relation to gastrointestinal development, homeostasis, and disease biology. We discuss other epigenetic mechanisms pertinent to the balance of trimethylation of lysine 27 on histone 3 and DNA methylation and their actions in gastrointestinal cancers. We also review the current molecular understanding of chromatin control in the pathogenesis of inflammatory bowel diseases.

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Overexpression of polycomb repressive complex 2 key components EZH2/SUZ12/EED as an unfavorable prognostic marker in cholangiocarcinoma

Cited by 16 publications

References 36 publications

ARID1A alterations and their clinical significance in cholangiocarcinoma

ARID1A alterations and their clinical significance in cholangiocarcinoma

Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

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