ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells.

Abstract

Chemotherapy resistance is an important problem for clinical therapy of osteosarcoma (OS). The potential effects of histone deacetylases (HDACs) on OS chemoresistance are studied. The expression of HDACs in OS cells resistance to doxorubicin (Dox) and cisplatin (CDDP) is checked. Among 11 members of HDACs, levels of HDAC6 are significantly upregulated in OS cells resistance to Dox and CDDP. Inhibition of HDAC6 via its specific inhibitor ACY1215 restores chemosensitivity of OS-resistant cells. Further, HDAC6 directly binds with estrogen-related receptors alpha (ERRα) to regulate its acetylation and protein stability. Inhibition of ERRα further strengthens ACY1215-increased chemosensitivity of OS-resistant cells. Mechanistically, K129 acetylation is the key residue for HDAC6-regulated protein levels of ERRα. Collectively, we find that ERRα contributes to HDAC6-induced chemoresistance of OS cells. Inhibition of HDAC6/ERRα axis might be a potential approach to overcome chemoresistance and improve therapy efficiency for OS treatment. 1. HDAC6 was significantly upregulated in Dox and CDDP resistant OS cells; 2. Inhibition of HDAC6 can restore chemosensitivity of OS cells; 3. HDAC6 binds with ERRα at K129 to decrease its acetylation and increase protein stability; 4. ERRα contributes to HDAC6-induced chemoresistance of OS cells.

• Authors: Qing He, Changzhi Yu, Yang Li, Peng Hao, Hantao Mai, Ruilian Guo, Guifang Zhong, Kelin Zhang, Chipiu Wong, Qian Chen, Yantao Chen
• Journal: Cell biology and toxicology (Cell Biol Toxicol) Vol. 39 Issue 3 Pg. 813-825 (06 2023) ISSN: 1573-6822 [Electronic] Switzerland
• PMID: 34524571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• ERRalpha estrogen-related receptor
• Cisplatin
• Doxorubicin
• HDAC6 protein, human
• Histone Deacetylase 6

Topics

• Humans
• Drug Resistance, Neoplasm
• Osteosarcoma (drug therapy, metabolism)
• Cisplatin (pharmacology)
• Doxorubicin (pharmacology)
• Cell Line, Tumor
• Bone Neoplasms (drug therapy, metabolism)
• Histone Deacetylase 6 (metabolism, pharmacology, therapeutic use)