PXD056645-1

PXD056645 is an original dataset announced via ProteomeXchange.

Title	NSD2 promotes HCC metastasis through methylating PKM2 and activating SF3B1-dependent alternative splicing
Description	Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
HostingRepository	PRIDE
AnnounceDate	2025-09-30
AnnouncementXML	Submission_2025-09-30_00:39:53.317.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dapeng zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetic acid derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-09 02:08:11	ID requested
⏵ 1	2025-09-30 00:39:53	announced

Dataset with its publication pending

submitter keyword: lactylation, SF3B1, methylation,NSD2, PKM2

dapeng zhang
contact affiliation	The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
contact email	dapengzhang0@yeah.net
lab head
Dapeng zhang
contact affiliation	The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
contact email	dapengzhang0@yeah.net
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056645
     1. Label: PRIDE project
     2. Name: NSD2 promotes HCC metastasis through methylating PKM2 and activating SF3B1-dependent alternative splicing