FAM63A sustains oncogenic PRC2 signaling through RBBP4 deubiquitination and creates an epigenetic vulnerability in cancer

ABSTRACT: Epigenetic gene silencing driven by Polycomb repressive complex 2 (PRC2) is a fundamental mechanism underlying tumor progression; however, how PRC2 activity is dynamically regulated by ubiquitin signaling remains incompletely understood. Here we identify the deubiquitinase FAM63A (MINDY1) as a critical regulator linking ubiquitin-mediated protein turnover to epigenetic repression in cancer. We show that FAM63A is significantly upregulated in lung cancer and promotes tumor cell proliferation and migration. Mechanistically, FAM63A directly interacts with and deubiquitinates the PRC2-associated protein RBBP4 by removing K48-linked polyubiquitin chains, thereby stabilizing RBBP4 and enhancing PRC2-dependent histone H3K27 trimethylation (H3K27me3). This epigenetic reprogramming leads to transcriptional repression of tumor suppressor genes and drives malignant progression. Disruption of FAM63A results in reduced H3K27me3 levels and reactivation of PRC2 target genes. Importantly, using FAM63A knockout mice, we demonstrate that loss of FAM63A markedly suppresses spontaneous tumor development across multiple cancer types, including lung, breast, and colon cancers, highlighting a conserved oncogenic role of this pathway. Furthermore, we identify MS31 as a small-molecule inhibitor that directly suppresses the enzymatic activity of FAM63A, destabilizes RBBP4, and disrupts the FAM63A–RBBP4–PRC2 epigenetic axis. Pharmacological inhibition of FAM63A by SY-7 effectively suppresses tumor cell proliferation and migration. Collectively, our findings reveal a previously unrecognized deubiquitination–epigenetic crosstalk mechanism driving tumorigenesis and establish FAM63A as a promising therapeutic target for cancer treatment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Peijing Zhang  

PROVIDER: PXD078653 | iProX | Wed May 20 00:00:00 BST 2026

REPOSITORIES: iProX