HMGA1 stimulates MYH9-dependent ubiquitination of GSK-3β via PI3K/Akt/c-Jun signaling to promote malignant progression and chemoresistance in gliomas

Cell Death Dis. 2021 Dec 10;12(12):1147. doi: 10.1038/s41419-021-04440-x.

Abstract

Myosin heavy chain 9 (MYH9) plays an essential role in human diseases, including multiple cancers; however, little is known about its role in gliomas. In the present study, we revealed that HMGA1 and MYH9 were upregulated in gliomas and their expression correlated with WHO grade, and HMGA1 promoted the acquisition of malignant phenotypes and chemoresistance of glioma cells by regulating the expression of MYH9 through c-Jun-mediated transcription. Moreover, MYH9 interacted with GSK-3β to inhibit the expression of GSK-3β protein by promoting its ubiquitination; the downregulation of GSK-3β subsequently promoted the nuclear translocation of β-catenin, enhancing growth, invasion, migration, and temozolomide resistance in glioma cells. Expression levels of HMGA1 and MYH9 were significantly correlated with patient survival and should be considered as independent prognostic factors. Our findings provide new insights into the role of HMGA1 and MYH9 in gliomagenesis and suggest the potential application of HMGA1 and MYH9 in cancer therapy in the future.

MeSH terms

  • Cell Proliferation / genetics
  • Drug Resistance, Neoplasm / genetics
  • Glioma* / drug therapy
  • Glioma* / genetics
  • Glycogen Synthase Kinase 3 beta* / genetics
  • Glycogen Synthase Kinase 3 beta* / metabolism
  • HMGA1a Protein* / genetics
  • HMGA1a Protein* / metabolism
  • Humans
  • Myosin Heavy Chains* / genetics
  • Myosin Heavy Chains* / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ubiquitination
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • HMGA1 protein, human
  • MYH9 protein, human
  • beta Catenin
  • HMGA1a Protein
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Myosin Heavy Chains