Downregulation of microRNA-6125 promotes colorectal cancer growth through YTHDF2-dependent recognition of N6-methyladenosine-modified GSK3β

Clin Transl Med. 2021 Oct;11(10):e602. doi: 10.1002/ctm2.602.


Background: MicroRNAs (miRNAs), the key regulator of gene expression, and N6-methyladenosine (m6A) RNA modification play a significant role in tumour progression. However, regulation of m6A-modified mRNAs by miRNAs in colorectal cancer (CRC), and its effect on progression of CRC, remains to be investigated.

Methods: Expression of miR-6125 and YTH Domain-Containing Family Protein 2 (YTHDF2) was detected by western blotting and immunohistochemistry. The effects of miR-6125 and YTHDF2 on proliferative capacity of CRC cells were analysed using soft agar, ATP, CCK8 and EdU assays, and in animal experiments.

Results: MiR-6125 expression was downregulated markedly in CRC, and expression correlated negatively with tumour size and prognosis. MiR-6125 targeted the 3'-UTR of YTHDF2 and downregulated the YTHDF2 protein, thereby increasing the stability of m6A-modified glycogen synthase kinase 3 beta (GSK3β) mRNA. Increased GSK3β protein levels inhibited the expression of Wnt/β-catenin/Cyclin D1 pathway-related proteins, leading to G0-G1 phase arrest and ultimately inhibiting the proliferation of CRC cells.

Conclusions: MiR-6125 regulates YTHDF2 and thus plays a critical role in regulating the Wnt/β-catenin pathway, thereby affecting the growth of CRC. Collectively, these results suggest that miR-6125 and YTHDF2 are potential targets for treatment of CRC.

Keywords: GSK3β; Wnt/β-catenin; YTHDF2; cell cycle; colorectal cancer; m6A; miR-6125.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / genetics
  • Adenosine / metabolism
  • Animals
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Disease Models, Animal
  • Down-Regulation / genetics*
  • Glycogen Synthase Kinase 3 beta / genetics*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism


  • MicroRNAs
  • RNA-Binding Proteins
  • YTHDF2 protein, human
  • N-methyladenosine
  • Glycogen Synthase Kinase 3 beta
  • Adenosine