PXD078653-1

PXD078653 is an original dataset announced via ProteomeXchange.

Title	FAM63A sustains oncogenic PRC2 signaling through RBBP4 deubiquitination and creates an epigenetic vulnerability in cancer
Description	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.
HostingRepository	iProX
AnnounceDate	2026-05-20
AnnouncementXML	Submission_2026-05-21_00:20:48.385.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Manyu Zhao
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2026-05-21 00:20:23	ID requested
⏵ 1	2026-05-21 00:20:48	announced

Dataset with its publication pending

submitter keyword: Deubiquitination, NSCLC, PRC2, H3K27 trimethylation

Peijing Zhang
contact affiliation	Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China
contact email	zhangpeijing@uestc.edu.cn
lab head
Manyu Zhao
contact affiliation	Tongji Hospital, Huazhong University of Science and Technology
contact email	myzhao.2025@foxmail.com
dataset submitter

iProX dataset URI