Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors

Author:

Chen Fan,Byrd Aria L.,Liu Jinpeng,Flight Robert M.ORCID,DuCote Tanner J.,Naughton Kassandra J.,Song Xiulong,Edgin Abigail R.ORCID,Lukyanchuk Alexsandr,Dixon Danielle T.,Gosser Christian M.,Esoe Dave-Preston,Jayswal Rani D.,Orkin Stuart H.ORCID,Moseley Hunter N. B.,Wang Chi,Brainson Christine FillmoreORCID

Abstract

AbstractInhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 could be suppressed by BET inhibition. Poorly differentiated human lung cancers were enriched for an H3K27me3-low state, representing a subtype that may benefit from BET inhibition as a single therapy or combined with additional EZH2 inhibition. These data highlight diverse roles of PRC2 in KRAS-driven lung adenocarcinomas, and demonstrate the utility of three-dimensional cultures for exploring epigenetic drug sensitivities for cancer.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences

American Cancer Society

American Association for Cancer Research

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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