PALI1 promotes tumor growth through competitive recruitment of PRC2 to G9A-target chromatin for dual epigenetic silencing

Ka wing Fong, Jonathan C. Zhao, Xiaodong Lu, Jung Kim, Andrea Piunti, Ali Shilatifard, Jindan Yu

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

PALI1 is a newly identified accessory protein of the Polycomb repressive complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here, we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to the PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators required for cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.

Original languageEnglish
Pages (from-to)4611-4626.e7
JournalMolecular Cell
Volume82
Issue number24
DOIs
StatePublished - Dec 15 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • ChIP-seq
  • Cut&Run
  • EED
  • EHMT1
  • EHMT2
  • ESC
  • EZH2
  • H3K27me3
  • H3K9me2
  • RNA-seq
  • SUZ12
  • histone methyltransferase
  • prostate cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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