AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma

Signal Transduct Target Ther. 2021 Jan 20;6(1):25. doi: 10.1038/s41392-020-00387-1.

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Although activator of HSP90 ATPase activity 1 (AHA1) is reported to be a potential oncogene, its role in osteosarcoma progression remains largely unclear. Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis, the relationship between AHA1 and cancer metabolism is unknown. In this study, we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients. AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo. Mechanistically, AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma. Notably, we identified that isocitrate dehydrogenase 1 (IDH1) is a novel client protein of Hsp90-AHA1. Furthermore, the IDH1 protein level was positively correlated with AHA1 in osteosarcoma. And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma. Moreover, high IDH1 level was also associated with poor prognosis of osteosarcoma patients. This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis, which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / enzymology*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Isocitrate Dehydrogenase / biosynthesis*
  • Isocitrate Dehydrogenase / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Chaperones / biosynthesis*
  • Molecular Chaperones / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Osteosarcoma / enzymology*
  • Osteosarcoma / genetics
  • Osteosarcoma / pathology
  • Up-Regulation*

Substances

  • AHSA1 protein, human
  • Molecular Chaperones
  • Neoplasm Proteins
  • Isocitrate Dehydrogenase
  • IDH1 protein, human