Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Sun, Xuxu; Wang, Sam C.; Wei, Yonglong; Luo, Xin; Jia, Yuemeng; Li, Lin; Gopal, Purva; Zhu, Min; Nassour, Ibrahim; Chuang, Jen Chieh; Maples, Thomas; Celen, Cemre; Nguyen, Liem H.; Wu, Linwei; Fu, Shunjun; Li, Weiping; Hui, Lijian; Tian, Feng; Ji, Yuan; Zhang, Shuyuan; Sorouri, Mahsa; Hwang, Tae Hyun; Letzig, Lynda; James, Laura E.; Wang, Zixi; Yopp, Adam C.; Singal, Amit G.; Zhu, Hao

doi:10.1016/j.ccell.2017.12.011

Cited by 51 publications

(34 citation statements)

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“…New mouse models are therefore required for further investigation of the oncogenic role of Arid1a in liver carcinogenesis. In turn, confirmation of such a role would corroborate a recent study showing that hepatic Arid1a can harbor either a tumor suppressor or oncogenic role depending on the cellular context ( Sun et al, 2018 ). An additional study also demonstrated that Arid1a is protumoral rather than a tumor suppressor in colorectal cancer with Apc mutations ( Mathur et al, 2017 ).…”

Section: Discussionsupporting

confidence: 75%

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ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

Riou

Ladli

Gerbal‐Chaloin

et al. 2020

eLife

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Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice genetically-invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of Arid1a together with β-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.

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Section: Discussionsupporting

confidence: 75%

“…In the adult mouse liver, Arid1a has been shown to play a role in liver regeneration and in tumorigenesis ( Sun et al, 2018 ; Sun et al, 2016 ). In human hepatocellular carcinoma (HCC), the most common primary liver cancer ( Torre et al, 2016 ), ARID1A is the chromatin modifier gene the most frequently inactivated (>13% of HCCs).…”

Section: Introductionmentioning

confidence: 99%

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

Riou

Ladli

Gerbal‐Chaloin

et al. 2020

eLife

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“…Because SWI/SNF machinery regulates chromatin conformation in an ATP‐dependent manner, their alterations are supposed to affect epigenetic changes in cancer cells; however, the biological roles of ARID1A/ARID2 mutations in HCC remain to be clarified. Recently, Sun et al reported context‐dependent roles of ARID1A in hepatocarcinogenesis by analyzing animal models. Axin 1 promotes degradation of CTNNB1 protein and negatively regulates WNT signaling.…”

Section: Driver Gene Landscape In the Largest Hcc Cohortmentioning

confidence: 99%

Molecular genomic landscapes of hepatobiliary cancer

Shibata

Arai²,

Totoki³

2018

Cancer Science

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Hepatocellular carcinoma (HCC) and biliary tract cancer are more frequent in East Asia including Japan than in Europe or North America. A compilation of 1340 multi‐ethnic HCC genomes, the largest cohort ever reported, identified a comprehensive landscape of HCC driver genes, comprised of three core drivers (TP53,TERT, and WNT signaling) and combinations of infrequent alterations in various cancer pathways. In contrast, five core driver genes (TP53,ARID1A,KRAS,SMAD4, and BAP1) with characteristic molecular alterations including fusion transcripts involving fibroblast growth factor receptor 2 and the protein kinase A pathway, and IDH1/2 mutation constituted the biliary tract cancer genomes. Consistent with their heterogeneous epidemiological backgrounds, mutational signatures and combinations of non‐core driver genes within these cancer genomes were found to be complex. Integrative analyses of multi‐omics data identified molecular classifications of these tumors that are associated with clinical outcome and enrichments of potential therapeutic targets, including immune checkpoint molecules. Translating comprehensive molecular‐genomic analysis together with further basic research and international collaborations are highly anticipated for developing precise and better treatments, diagnosis, and prevention of these tumor types.

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“…TFs covariance network analysis showed that the three clusters demonstrate different transcriptional regulatory status (Figure 4D). Significantly, MYC , ARID1A , TBX3 , and SOX11 are highly expressed in tumor cells, where, besides the well‐known MYC that is recently reported to be overexpressed in human prostatic basal cells, 19 the oncogenic role of ARID1A , a key component of chromatin remodeling complex SWI/SNF, has been recently demonstrated in liver cancer; 41 the development‐related gene SOX11 was reported to be elevated in basal‐like breast cancer; 42 and TBX3 plays important roles in development, differentiation, and tumorigenesis 43 . The TFs covariance network provides clues to future dissection of the regulatory mechanism of BCC.…”

Section: Resultsmentioning

confidence: 99%

Mutational and transcriptomic landscapes of a rare human prostate basal cell carcinoma

Long

Jiang

et al. 2020

The Prostate

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Background As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization. Methods Here, we applied single‐cell genomic amplification and RNA‐Seq to a specimen of human prostate BCC (CK34βE12+/P63+/PAP−/PSA−). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the transcriptomes of 69 single cells were also obtained. Results The five putative driver genes mutated in BCC are CASC5, NUTM1, PTPRC, KMT2C, and TBX3, and the top three nucleotide substitutions are C>T, T>C, and C>A, similar to common prostate cancer. The distribution of the variant allele frequency values indicated that these single cells are from the same tumor clone. The 69 single cells were clustered into tumor, stromal, and immune cells based on their global transcriptomic profiles. The tumor cells specifically express basal cell markers like KRT5, KRT14, and KRT23 and epithelial markers EPCAM, CDH1, and CD24. The transcription factor covariance network analysis showed that the BCC tumor cells have distinct regulatory networks. By comparison with current prostate cancer datasets, we found that some of the bulk samples exhibit basal cell signatures. Interestingly, at single‐cell resolution the gene expression patterns of prostate BCC tumor cells show uniqueness compared with that of common prostate cancer‐derived circulating tumor cells. Conclusions This study, for the first time, discloses the comprehensive mutational and transcriptomic landscapes of prostate BCC, which lays a foundation for the understanding of its tumorigenesis mechanism and provides new insights into prostate cancers in general.

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Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Cited by 51 publications

References 1 publication

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

Molecular genomic landscapes of hepatobiliary cancer

Mutational and transcriptomic landscapes of a rare human prostate basal cell carcinoma

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