PXD050308

PXD050308 is an original dataset announced via ProteomeXchange.

Title	Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma
Description	BRAFV600E mutant melanomas treated with BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) almost invariably develop drug resistance (DTR). Restored glycolysis has been frequently found in clinical targeted therapy-resistant melanoma biopsies. LDH, catalyzing the last step of glycolysis, is negatively correlated with clinical outcome of melanoma patients receiving BRAFi target therapy. How resumed glycolysis controls the emergence of acquired resistance, especially via intrinsic mechanisms that circumvent the BRAF/MEK module, remains unknown. Here, we identify lactylation of LSD1, induced by re-accumulated lactate in DTR melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with FosL1, thereby preventing its ubiquitination and degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21). In DTR melanoma cells, chromatin binding capacity of FosL1 was significantly strengthened due to reduced acetylation, which in turn increases selective chromatin enrichment of LSD1. We further demonstrate that lactylated LSD1 co-orchestrates gene transcription with FosL1 to repress ferroptosis in DTR cells via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibitor (LSD1i) activates ferroptosis, resulting in drastic DTR melanoma regression in mice. Importantly, LSD1i-induced immunogenic ferroptosis synergizes with immune checkpoint blockade (ICB) in vivo. Together, our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in DTR melanoma, which provides a therapeutically actionable strategy to overcome acquired resistance to targeted therapy.
HostingRepository	iProX
AnnounceDate	2024-03-04
AnnouncementXML	Submission_2025-02-13_18:40:40.312.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Aicun Li
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	ubiquitination signature dipeptidyl lysine; acetylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-03 23:24:30	ID requested
⏵ 1	2025-02-13 18:40:40	announced

Dataset with its publication pending

submitter keyword: lactylation, epigenetic, drug resistance

Han You
contact affiliation	Xiamen University
contact email	hyou@xmu.edu.cn
lab head
Aicun Li
contact affiliation	Xiamen University
contact email	liaicun@stu.xmu.edu.cn
dataset submitter

iProX dataset URI