2. Academic Validation
  3. Gain-of-function mutations in the catalytic domain of DOT1L promote lung cancer malignant phenotypes via the MAPK/ERK signaling pathway

Gain-of-function mutations in the catalytic domain of DOT1L promote lung cancer malignant phenotypes via the MAPK/ERK signaling pathway

  • Sci Adv. 2023 Jun 2;9(22):eadc9273. doi: 10.1126/sciadv.adc9273.
Jiayu Zhang 1 2,  Ting Yang 1 2,  Mei Han 1 2,  Xiaoxuan Wang 1 2,  Weiming Yang 1 2,  Ning Guo 1 2,  Yong Ren 3,  Wei Cui 1,  Shangxiao Li 4,  Yongshan Zhao 4,  Xin Zhai 5,  Lina Jia 1,  Jingyu Yang 1,  Chunfu Wu 1,  Lihui Wang 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi 117004, China.
  • 3 Department of Pathology, General Hospital of Central Theater Command of People's Liberation Army, Wuhan 430070, China.
  • 4 Department of Biochemistry and Molecular Biology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 5 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 37256945 DOI: 10.1126/sciadv.adc9273
Abstract

Lung Cancer is a lethal malignancy lacking effective therapies. Emerging evidence suggests that epigenetic Enzyme mutations are closely related to the malignant phenotype of lung Cancer. Here, we identified a series of gain-of-function mutations in the Histone Methyltransferase DOT1L. The strongest of them is R231Q, located in the catalytic DOT domain. R231Q can enhance the substrate binding ability of DOT1L. Moreover, R231Q promotes cell growth and drug resistance of lung Cancer cells in vitro and in vivo. Mechanistic studies also revealed that the R231Q mutant specifically activates the MAPK/ERK signaling pathway by enriching H3K79me2 on the RAF1 promoter and epigenetically regulating the expression of downstream targets. The combination of a DOT1L Inhibitor (SGC0946) and a MAPK/ERK axis inhibitor (binimetinib) can effectively reverse the R231Q-induced phenomena. Our results reveal gain-of-function mutations in an epigenetic Enzyme and provide promising insights for the precise treatment of lung Cancer patients.

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