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CDKN2A CpG 岛的超甲基化导致 SWI/SNF 功能丧失型肿瘤对 PRC2 抑制剂产生耐药性。

Hypermethylation of CDKN2A CpG island drives resistance to PRC2 inhibitors in SWI/SNF loss-of-function tumors.

机构信息

Department of Thoracic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.

Blueray Biopharma Inc., Shanghai, China.

出版信息

Cell Death Dis. 2024 Nov 5;15(11):794. doi: 10.1038/s41419-024-07109-3.

DOI:10.1038/s41419-024-07109-3
PMID:39500892
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11538500/
Abstract

Polycomb repressive complex 2 (PRC2) catalyzes the writing of the tri-methylated histone H3 at Lys27 (H3K27me3) epigenetic marker and suppresses the expression of genes, including tumor suppressors. The function of the complex can be partially antagonized by the SWI/SNF chromatin-remodeling complex. Previous studies have suggested that PRC2 is important for the proliferation of tumors with SWI/SNF loss-of-function mutations. In the present study, we have developed an EED-directed allosteric inhibitor of PRC2 termed BR0063, which exhibits anti-proliferative properties in a subset of solid tumor cell lines harboring mutations of the SWI/SNF subunits, SMARCA4 or ARID1A. Tumor cells sensitive to BR0063 exhibited several distinct phenotypes, including cell senescence, which was mediated by the up-regulation of CDKN2A/p16. Further experiments revealed that the expression of p16 was suppressed in the BR0063-resistant cells via DNA hypermethylation in the CpG island (CGI) promoter region, rather than via PRC2 occupancy. The expression of TET1, which is required for DNA demethylation, was found to be inversely correlated with p16 CGI methylation, and this may serve as a biomarker for the prediction of resistance to PRC2 inhibitors in SWI/SNF LOF tumors.

摘要

多梳抑制复合物 2 (PRC2) 催化组蛋白 H3 在赖氨酸 27 位的三甲基化 (H3K27me3) 表观遗传标记的书写，并抑制基因的表达，包括肿瘤抑制基因。该复合物的功能可部分被 SWI/SNF 染色质重塑复合物拮抗。先前的研究表明，PRC2 对于具有 SWI/SNF 功能丧失突变的肿瘤的增殖很重要。在本研究中，我们开发了一种针对 EED 的 PRC2 别构抑制剂，称为 BR0063，它在携带 SWI/SNF 亚基 SMARCA4 或 ARID1A 突变的部分实体瘤细胞系中表现出抗增殖特性。对 BR0063 敏感的肿瘤细胞表现出几种不同的表型，包括细胞衰老，这是由 CDKN2A/p16 的上调介导的。进一步的实验表明，BR0063 耐药细胞中 p16 的表达通过 CpG 岛 (CGI) 启动子区域的 DNA 超甲基化而不是通过 PRC2 占据被抑制。需要 DNA 去甲基化的 TET1 的表达被发现与 p16 CGI 甲基化呈负相关，这可能作为预测 SWI/SNF LOF 肿瘤中对 PRC2 抑制剂耐药的生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/537b48858f53/41419_2024_7109_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/370f0dc224bf/41419_2024_7109_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/ad16c6be8ab5/41419_2024_7109_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/17bab5804f87/41419_2024_7109_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/9c2d32258d87/41419_2024_7109_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/4020524f50ab/41419_2024_7109_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/537b48858f53/41419_2024_7109_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/370f0dc224bf/41419_2024_7109_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/ad16c6be8ab5/41419_2024_7109_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/17bab5804f87/41419_2024_7109_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/9c2d32258d87/41419_2024_7109_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/4020524f50ab/41419_2024_7109_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0756/11538500/537b48858f53/41419_2024_7109_Fig6_HTML.jpg

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