HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1

Cell Death Dis. 2023 May 16;14(5):327. doi: 10.1038/s41419-023-05849-2.

Abstract

Epithelial-mesenchymal transition (EMT) is associated with the invasive and metastatic phenotypes in colorectal cancer (CRC). However, the mechanisms underlying EMT in CRC are not completely understood. In this study, we find that HUNK inhibits EMT and metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at serine 645 (S645) site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK-1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Colorectal Neoplasms* / genetics
  • Epithelial-Mesenchymal Transition* / genetics
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Neoplasm Metastasis
  • Phosphorylation / physiology
  • Protein Serine-Threonine Kinases / metabolism
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • Actins
  • RHOA protein, human
  • rhoA GTP-Binding Protein
  • HUNK protein, human
  • Protein Serine-Threonine Kinases