ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression

Luo, Qingyu; Wu, Xiaowei; Chang, Wan; Zhao, Pengfei; Zhu, Xiaolin; Chen, Hongyan; Nan, Yabing; Luo, Aiping; Xu, Zhou; Su, Dan; Jiao, Wenjie; Liu, Zhihua

doi:10.1158/0008-5472.can-18-2446

Cited by 23 publications

(12 citation statements)

References 44 publications

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“…Loss of ARID1A expression can also be a result of ARID1A promoter hypermethylation [ 20 ], and it is likely that tumors use sequence mutations in both alleles, or promoter hypermethylation together with mutations in different alleles, to drive complete loss of ARID1A proteins, following the classical “two-hit” theory characterizing tumor suppressor genes. The resultant loss of ARID1A expression impairs the interaction of ARID1A with other SWI/SNF subunits in the nucleus [ 11 ].…”

Section: Arid1a As a Tumor Suppressormentioning

confidence: 99%

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Mandal

Wang

et al. 2022

J Biomed Sci

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Chromatin remodeling is an essential cellular process for organizing chromatin structure into either open or close configuration at specific chromatin locations by orchestrating and modifying histone complexes. This task is responsible for fundamental cell physiology including transcription, DNA replication, methylation, and damage repair. Aberrations in this activity have emerged as epigenomic mechanisms in cancer development that increase tumor clonal fitness and adaptability amidst various selection pressures. Inactivating mutations in AT-rich interaction domain 1A (ARID1A), a gene encoding a large nuclear protein member belonging to the SWI/SNF chromatin remodeling complex, result in its loss of expression. ARID1A is the most commonly mutated chromatin remodeler gene, exhibiting the highest mutation frequency in endometrium-related uterine and ovarian carcinomas. As a tumor suppressor gene, ARID1A is essential for regulating cell cycle, facilitating DNA damage repair, and controlling expression of genes that are essential for maintaining cellular differentiation and homeostasis in non-transformed cells. Thus, ARID1A deficiency due to somatic mutations propels tumor progression and dissemination. The recent success of PARP inhibitors in treating homologous recombination DNA repair-deficient tumors has engendered keen interest in developing synthetic lethality-based therapeutic strategies for ARID1A-mutated neoplasms. In this review, we summarize recent advances in understanding the biology of ARID1A in cancer development, with special emphasis on its roles in DNA damage repair. We also discuss strategies to harness synthetic lethal mechanisms for future therapeutics against ARID1A-mutated cancers.

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Section: Arid1a As a Tumor Suppressormentioning

confidence: 99%

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Mandal

Wang

et al. 2022

J Biomed Sci

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“…Second, in addition to mutation, promoter hypermethylation of ARID1A gene has been reported in various human diseases. 35 , 36 , 37 It is possible that the decrease of ARID1A in DM patients can be induced by aberrant epigenetic regulation. Third, ARID1A reduction may contribute to β cell senescence.…”

Section: Discussionmentioning

confidence: 99%

ARID1A loss in pancreas leads to islet developmental defect and metabolic disturbance

Kuo¹,

Cheng²,

Chen³

et al. 2023

iScience

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“…A putative C2TSG that has recently been identified in liver cancer is the well-known (mutated) tumor suppressor gene ARID1A . While a relationship between ARID1A promoter hypermethylation and disease progression had been shown before for squamous cell carcinoma [ 66 ], the situation was unclear for hepatocellular carcinoma (HCC). However, a recent study analyzing the TCGA data set could show that low ARID1A expression in HCC is clearly associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

Dahl

Villwock

Habenberger

et al. 2022

Cancers

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The aim of our proposed concept is to find new target structures for combating cancers with unmet medical needs. This, unfortunately, still applies to the majority of the clinically most relevant tumor entities such as, for example, liver cancer, pancreatic cancer, and many others. Current target structures almost all belong to the class of oncogenic proteins caused by tumor-specific genetic alterations, such as activating mutations, gene fusions, or gene amplifications, often referred to as cancer “driver alterations” or just “drivers.” However, restoring the lost function of tumor suppressor genes (TSGs) could also be a valid approach to treating cancer. TSG-derived proteins are usually considered as control systems of cells against oncogenic properties; thus, they represent the brakes in the “car-of-life.” Restoring these tumor-defective brakes by gene therapy has not been successful so far, with a few exceptions. It can be assumed that most TSGs are not being inactivated by genetic alteration (class 1 TSGs) but rather by epigenetic silencing (class 2 TSGs or short “C2TSGs”). Reactivation of C2TSGs in cancer therapy is being addressed by the use of DNA demethylating agents and histone deacetylase inhibitors which act on the whole cancer cell genome. These epigenetic therapies have neither been particularly successful, probably because they are “shotgun” approaches that, although acting on C2TSGs, may also reactivate epigenetically silenced oncogenic sequences in the genome. Thus, new strategies are needed to exploit the therapeutic potential of C2TSGs, which have also been named DNA methylation cancer driver genes or “DNAme drivers” recently. Here we present a concept for a new translational and therapeutic approach that focuses on the phenotypic imitation (“mimesis”) of proteins encoded by highly disease-relevant C2TSGs/DNAme drivers. Molecular knowledge on C2TSGs is used in two complementary approaches having the translational concept of defining mimetic drugs in common: First, a concept is presented how truncated and/or genetically engineered C2TSG proteins, consisting solely of domains with defined tumor suppressive function can be developed as biologicals. Second, a method is described for identifying small molecules that can mimic the effect of the C2TSG protein lost in the cancer cell. Both approaches should open up a new, previously untapped discovery space for anticancer drugs.

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ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression

Cited by 23 publications

References 44 publications

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

ARID1A loss in pancreas leads to islet developmental defect and metabolic disturbance

White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

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