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Updated: Oct 20, 2025
Author Spotlight: RNA FISH for Locating lncRNA-SNHG6 in Osteosarcoma Cells
Published on: June 16, 2023
ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells
Qing He1, Changzhi Yu2, Yang Li3
1Department of Surgical Intensive Care Unit, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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.
Insights
Histone deacetylase 6 (HDAC6) is upregulated in osteosarcoma (OS) cells resistant to chemotherapy. Inhibiting HDAC6 or its interaction with estrogen-related receptor alpha (ERRα) can restore sensitivity to chemotherapy drugs.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy resistance significantly hinders effective osteosarcoma (OS) treatment.
- Histone deacetylases (HDACs) are implicated in various cellular processes, including drug resistance.
Purpose of the Study:
- To investigate the role of HDACs, specifically HDAC6, in chemoresistance of osteosarcoma.
- To explore the therapeutic potential of targeting the HDAC6/estrogen-related receptor alpha (ERRα) axis.
Main Methods:
- Assessed HDAC expression in chemoresistant OS cells.
- Utilized HDAC6 inhibitor (ACY1215) and ERRα inhibition to evaluate chemosensitivity.
- Investigated the interaction between HDAC6 and ERRα using co-immunoprecipitation and acetylation site analysis.
Main Results:
- HDAC6 expression was significantly upregulated in OS cells resistant to doxorubicin (Dox) and cisplatin (CDDP).
- Inhibition of HDAC6 using ACY1215 restored chemosensitivity in resistant OS cells.
- HDAC6 directly binds to ERRα at lysine 129 (K129), decreasing its acetylation and increasing protein stability, thereby promoting chemoresistance.
Conclusions:
- HDAC6 plays a crucial role in mediating chemoresistance in osteosarcoma.
- The interaction between HDAC6 and ERRα is a key mechanism driving chemoresistance.
- Targeting the HDAC6/ERRα pathway presents a promising therapeutic strategy to overcome chemoresistance in osteosarcoma.
