Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer

Cell Rep. 2023 Sep 26;42(9):113003. doi: 10.1016/j.celrep.2023.113003. Epub 2023 Sep 8.


Oncogenic KRAS mutations are a key driver for initiation and progression in non-small cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, is recruited and promotes KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results define a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.

Keywords: CP: Cancer; CP: Molecular biology; KRAS; RABGEF1; SETD7; lysine methylation; non-small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Guanine Nucleotide Exchange Factors / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Lung Neoplasms* / pathology
  • Methylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism


  • Proto-Oncogene Proteins p21(ras)
  • Histone-Lysine N-Methyltransferase
  • KRAS protein, human
  • SETD7 protein, human
  • RABGEF1 protein, human
  • Guanine Nucleotide Exchange Factors