BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity

Kim, Eui-Jun; Liu, Peng; Zhang, Shengjie; Donahue, Kristine; Wang, Yidan; Schehr, Jennifer L.; Wolfe, Serena K.; Dickerson, Amber; Lü, Li; Li, Rui; Zhong, Xuehua; Wisinski, Kari B.; Yu, Min; Suzuki, Aussie; Lang, Joshua M.; Ong, Irene M.; Xu, Wei

doi:10.1093/nar/gkab1122

Cited by 40 publications

(34 citation statements)

References 56 publications

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“…Although previous studies have shown that the BD1 could be phosphorylated at Y97/Y98 by JAK2 and methylated at K99 by SETD6, these PTMs do not affect the BD1 binding to acetylated histones ( 57 , 58 ). Another study showed that PRMT4 inhibitors decreased BRD4 genomic occupancy at the super-enhancers likely by disrupting the interaction between methylated BAF155 and BRD4 ( 59 ). However, this is not the sole mechanism underlying PRMT4-mediated regulation of BRD4 because less than 6% of BRD4 forms a complex with methylated BAF155 as shown in their study.…”

Section: Discussionmentioning

confidence: 99%

Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair

et al. 2022

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BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4 functions on transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interacts with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 recruitment to acetylated histones/chromatin. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation–dependent regulatory mechanism of BRD4 and highlight targeting PRMT2/4 for better antitumor effect of BET inhibitors and DNA damaging agents.

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Section: Discussionmentioning

confidence: 99%

Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair

et al. 2022

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“…The majority of genes related to super enhancers are specific for determining cellular properties. Moreover, SEs have been proven to exert an essential role in cancer development ( Chen et al, 2018 ), cell differentiation ( Debek and Juszczynski, 2022 ) and immune response ( Kim et al, 2021 ). In this study we found the super enhancer activity was responsible for PRR7-AS1 overexpression in tumors.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis of super enhancer-induced PRR7-AS1 as a potential prognostic and immunological biomarker

Wang

Liu

et al. 2023

Front. Genet.

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Introduction: Systematic pan-cancer analysis of the roles and regulatory mechanisms for PRR7-AS1 is currently not available.Methods: In the present study, a comprehensive bioinformatic approach was used to mine the underlying oncogenic effects of PRR7-AS1, including expression status, prognostic value and immune characteristics.Results: We discovered that PRR7-AS1 expression was remarkably upregulated in most cancer types and exhibited a negative correlation with the prognosis. Furthermore, PRR7-AS1 expression was inversely connected with the majority of tumor-infiltrating immune cells, immune scores and immune checkpoint gene expression in pancancer. There was also a significant correlation between PRR7-AS1 expression status and tumor mutational burden, microsatellite instability, and neoantigens in certain tumors. PRR7-AS1 had the best predictive power for immune checkpoint blockade efficacy compared to other well-recognized biomarkers. PRR7-AS1 overexpression could affect cytotoxic T cells-mediated antitumor responses. Functional enrichment analysis revealed that PRR7-AS1 might be involved in the metabolic pathways. Super enhancer activity might have participated in the regulation of PRR7-AS1 expression. And we constructed the competitive endogenous RNA networks for PRR7-AS1.Discussion: In general, PRR7-AS1 had the potential to be a diagnostic, prognostic and immune biomarker for pan cancer. PRR7-AS1 was correlated with an immunosuppressive microenvironment and was a new potential target for immunotherapy. Epigenetic factors were the driving forces for PRR7-AS1 overexpression in tumors.

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“…CARM1 and interacts with XBP1 to modulatie the ER stress response in the IRE1α/XBP1 pathway, triggering an immunosuppressive environment ( 78 ). Furthermore, CARM1 mainly targets BAF155 in triple-negative breast cancer by inhibiting the interferon pathway to inhibit the host immune response ( 79 ). Similarly, CARM1 is positively regulated by circHMGB2, which inhibits type I interferon responses and downstream genes.…”

Section: Classification and Biological Functions Of Histone Methyltra...mentioning

confidence: 99%

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

Zhang

Chen²,

Liu³

et al. 2023

Front. Immunol.

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Epigenetic modifications may alter the proliferation and differentiation of normal cells, leading to malignant transformation. They can also affect normal stimulation, activation, and abnormal function of immune cells in the tissue microenvironment. Histone methylation, coordinated by histone methylase and histone demethylase to stabilize transcription levels in the promoter area, is one of the most common types of epigenetic alteration, which gained increasing interest. It can modify gene transcription through chromatin structure and affect cell fate, at the transcriptome or protein level. According to recent research, histone methylation modification can regulate tumor and immune cells affecting anti-tumor immune response. Consequently, it is critical to have a thorough grasp of the role of methylation function in cancer treatment. In this review, we discussed recent data on the mechanisms of histone methylation on factors associated with immune resistance of tumor cells and regulation of immune cell function.

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BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity

Cited by 40 publications

References 56 publications

Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair

Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair

Pan-cancer analysis of super enhancer-induced PRR7-AS1 as a potential prognostic and immunological biomarker

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

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