默克尔细胞多瘤病毒激活 LSD1 介导的非典型 BAF 阻断以调节转化和肿瘤发生。
Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis.
机构信息
Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
出版信息
Nat Cell Biol. 2020 May;22(5):603-615. doi: 10.1038/s41556-020-0503-2. Epub 2020 Apr 13.
Merkel cell carcinoma (MCC)-a neuroendocrine cancer of the skin-is caused by the integration of Merkel cell polyomavirus and persistent expression of large T antigen and small T antigen. We report that small T antigen in complex with MYCL and the EP400 complex activates the expression of LSD1 (KDM1A), RCOR2 and INSM1 to repress gene expression by the lineage transcription factor ATOH1. LSD1 inhibition reduces the growth of MCC in vitro and in vivo. Through a forward-genetics CRISPR-Cas9 screen, we identified an antagonistic relationship between LSD1 and the non-canonical BAF (ncBAF) chromatin remodelling complex. Changes in gene expression and chromatin accessibility caused by LSD1 inhibition were partially rescued by BRD9 inhibition, revealing that LSD1 and ncBAF antagonistically regulate an overlapping set of genes. Our work provides mechanistic insight into the dependence of MCC on LSD1 and a tumour suppressor role for ncBAF in cancer.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种皮肤神经内分泌癌，由默克尔细胞多瘤病毒整合和大 T 抗原及小 T 抗原的持续表达引起。我们报告称，小 T 抗原与 MYCL 和 EP400 复合物结合，激活 LSD1（KDM1A）、RCOR2 和 INSM1 的表达，从而抑制谱系转录因子 ATOH1 的基因表达。LSD1 抑制可减少 MCC 在体外和体内的生长。通过正向遗传学 CRISPR-Cas9 筛选，我们发现 LSD1 与非典型 BAF（ncBAF）染色质重塑复合物之间存在拮抗关系。LSD1 抑制引起的基因表达和染色质可及性变化部分可通过 BRD9 抑制得到挽救，表明 LSD1 和 ncBAF 拮抗地调节一组重叠的基因。我们的工作为 MCC 对 LSD1 的依赖性提供了机制上的见解，并揭示了 ncBAF 在癌症中作为肿瘤抑制因子的作用。
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