2. Academic Validation
  3. Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma

Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma

  • Dev Cell. 2025 Jul 21;60(14):1974-1990.e11. doi: 10.1016/j.devcel.2025.02.016.
Aicun Li 1,  Zhicheng Gong 2,  Yuhan Long 1,  Yuanpei Li 3,  Chen Liu 1,  Xiao Lu 1,  Qing Li 1,  Xiaoniu He 4,  Hezhe Lu 5,  Kaichun Wu 6,  Yongzhan Nie 6,  Jing Tan 7,  Jing Ye 8,  Han You 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361104, P.R. China.
  • 2 Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China.
  • 3 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.
  • 4 Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, P.R. China.
  • 5 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P.R. China.
  • 6 State Key Laboratory of Holistic Integrative Management of Gastro intestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
  • 7 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
  • 8 Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China. Electronic address: yejing@fmmu.edu.cn.
  • 9 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361104, P.R. China. Electronic address: hyou@xmu.edu.cn.
PMID: 40132584 DOI: 10.1016/j.devcel.2025.02.016
Abstract

BRAFV600E mutant melanomas treated with BRAF inhibitor (BRAFi) and MEK Inhibitor (MEKi) almost invariably develop drug resistance, accompanied by restored glucose metabolism. How resumed glycolysis controls acquired resistance remains unknown. Here, we identify that lysine-specific demethylase 1 (LSD1) lactylation, induced by re-accumulated lactate in both human and murine BRAFi/MEKi-resistant melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with Fos-related antigen 1 (FosL1), preventing its degradation by E3 Ligase tripartite-motif-containing protein 21 (TRIM21) and selectively enhancing its genomic enrichment. We further demonstrate that lactylated LSD1 co-directs gene transcription with FosL1 to repress Ferroptosis via interfering with Transferrin Receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibition activates Ferroptosis, resulting in drastic regression of drug-resistant murine melanoma when combined with immunotherapy. Our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in BRAFi/MEKi-resistant melanoma, providing a therapeutically actionable strategy to overcome resistance to targeted therapy and immunotherapy.

Keywords

BRAFV600E melanoma; FosL1; LSD1; epigenetic reprogramming; ferroptosis; immunotherapy; lactylation; metabolic reprogramming; targeted-therapy resistance; ubiquitination.

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