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ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells

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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.

Graphical abstract

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.

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All data generated or analyzed during this study are included in this published article.

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Funding

The present study was supported by the Science and Technology Program of Guangzhou (no. 201804010312) and the Science and Technology Program of Zengcheng District (no. ZCKJ2019-014).

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Authors and Affiliations

  1. Department of Surgical Intensive Care Unit, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Qing He, Peng Hao, Hantao Mai, Ruilian Guo, Guifang Zhong & Kelin Zhang

  2. Department of Chinese Traditional Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Changzhi Yu

  3. Pediatric Hematology and Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Yang Li

  4. Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107, Yanjiang West Road, Yuexiu District, Guangzhou, 510120, China

    Chipiu Wong, Qian Chen & Yantao Chen

Authors
  1. Qing He
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  2. Changzhi Yu
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  3. Yang Li
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  4. Peng Hao
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  10. Qian Chen
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  11. Yantao Chen
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Contributions

Data collecting—Qing He, Changzhi Yu, Yang Li, Peng Hao, Hantao Mai.

Writing—Qing He, Changzhi Yu, Chipiu Wong, Qian Chen, Chen Yantao.

Data analysis—Qing He, Hantao Mai, Ruilian Guo, Guifang Zhong, Kelin Zhang, Chipiu Wong.

Design—Qing He, Changzhi Yu, Yang Li, Chen Yantao.

Corresponding author

Correspondence to Yantao Chen.

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Animal study was approved by Sun Yat-sen University School of Medicine Animal Care and Use Committee.

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He, Q., Yu, C., Li, Y. et al. ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells. Cell Biol Toxicol 39, 813–825 (2023). https://doi.org/10.1007/s10565-021-09651-8

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  • DOI: https://doi.org/10.1007/s10565-021-09651-8

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