PXD054525

PXD054525 is an original dataset announced via ProteomeXchange.

Title	Josephin Domain Containing 2 (JOSD2) Inhibition as Pan-KRAS-Mutation-Targeting Strategy for Colorectal Cancer
Description	KRAS is the most common mutated oncogenes in colorectal cancer (CRC), yet effective therapeutic strategies for targeting multiple KRAS-mutations remained challenging. The prolonged protein stability of KRAS mutants contribute to their robust tumor-promoting effects, but the underlying mechanism is elusive. Herein by screening deubiquitinases (DUBs) siRNA library, we identified Josephin domain containing 2 (JOSD2) functions as a potent DUB that regulates the protein stability of KRAS mutants. Mechanistically, JOSD2 directly interacted with and stabilized KRAS variants across different mutants, by reverting their proteolytic ubiquitination; while KRAS mutants reciprocally inhibited the catalytic activity of CHIP, a bona fide E3 ubiquitin ligase for JOSD2, thus forming a JOSD2/KRAS positive feedback circuit that significantly accelerated KRAS-mutant CRC growth. Inhibition of JOSD2 by RNA interference or its pharmacological inhibitor promoted the polyubiquitination and proteasomal degradation of KRAS mutants, and preferentially impeded the growth of KRAS-mutant CRC including patient-derived cells/xenografts/organoids (PDCs/PDXs/PDOs) over that harboring wild-type KRAS. Collectively, this study not only revealed the crucial roles of JOSD2/KRAS positive feedback circuit in KRAS-mutant CRC, but also provides a rationale to target JOSD2 as the promising pan-KRAS-mutation-targeting strategy for the treatment of a broad population of CRC patients with KRAS variant across different mutant types.
HostingRepository	PRIDE
AnnounceDate	2025-03-01
AnnouncementXML	Submission_2025-03-01_02:56:12.689.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tao Yuan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-02 01:26:48	ID requested
⏵ 1	2025-03-01 02:56:13	announced

Dataset with its publication pending

submitter keyword: deubiquitinases, ubiquitination., JOSD2, KRAS, colorectal cancer

Anonymity Anonymity
contact affiliation	Anonymity for double-blind review
contact email	Anonymity for double-blind review
lab head
Tao Yuan
contact affiliation	Zhejiang University
contact email	11919006@zju.edu.cn
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/03/PXD054525

PRIDE project URI

• PRIDE
  1. PXD054525
     1. Label: PRIDE project
     2. Name: Josephin Domain Containing 2 (JOSD2) Inhibition as Pan-KRAS-Mutation-Targeting Strategy for Colorectal Cancer