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PXD050308

PXD050308 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleLactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma
DescriptionBRAFV600E 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.
HostingRepositoryiProX
AnnounceDate2024-03-04
AnnouncementXMLSubmission_2025-02-13_18:40:40.312.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterAicun Li
SpeciesList scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationListubiquitination signature dipeptidyl lysine; acetylated residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-03-03 23:24:30ID requested
12025-02-13 18:40:40announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: lactylation, epigenetic, drug resistance
Contact List
Han You
contact affiliationXiamen University
contact emailhyou@xmu.edu.cn
lab head
Aicun Li
contact affiliationXiamen University
contact emailliaicun@stu.xmu.edu.cn
dataset submitter
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iProX dataset URI