학술논문
Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis
Document Type
Academic Journal
Author
Source
Nature Cell Biology. May 2020, Vol. 22 Issue 5, p603, 13 p.
Subject
Language
English
ISSN
1465-7392
Abstract
Author(s): Donglim Esther Park [sup.1] [sup.2], Jingwei Cheng [sup.2] [sup.3], John P. McGrath [sup.4], Matthew Y. Lim [sup.1] [sup.5], Camille Cushman [sup.1] [sup.2], Selene K. Swanson [sup.6], Michelle L. Tillgren [...]
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. Park et al. show that Merkel cell polyomavirus upregulates LSD1 activity to repress differentiation genes that can be activated by non-canonical BAF, thereby modulating transformation and tumorigenesis in Merkel cell carcinoma.
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. Park et al. show that Merkel cell polyomavirus upregulates LSD1 activity to repress differentiation genes that can be activated by non-canonical BAF, thereby modulating transformation and tumorigenesis in Merkel cell carcinoma.