ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells,Cell Biology and Toxicology

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ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-09-15 , DOI: 10.1007/s10565-021-09651-8
Qing He ₁ , Changzhi Yu ₂ , Yang Li ₃ , Peng Hao ₁ , Hantao Mai ₁ , Ruilian Guo ₁ , Guifang Zhong ₁ , Kelin Zhang ₁ , Chipiu Wong ₄ , Qian Chen ₄ , Yantao Chen ₄

Affiliation

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.

中文翻译：

ERRα 有助于 HDAC6 诱导的骨肉瘤细胞化疗耐药

化疗耐药是骨肉瘤（OS）临床治疗的重要问题。研究了组蛋白脱乙酰酶 (HDAC) 对 OS 化疗耐药性的潜在影响。检查对阿霉素 (Dox) 和顺铂 (CDDP) 耐药的 OS 细胞中 HDAC 的表达。在 HDAC 的 11 个成员中，HDAC6 的水平在 OS 细胞对 Dox 和 CDDP 的耐药性中显着上调。通过其特异性抑制剂 ACY1215 抑制 HDAC6 可恢复 OS 耐药细胞的化疗敏感性。此外，HDAC6 直接与雌激素相关受体 α (ERRα) 结合，调节其乙酰化和蛋白质稳定性。 ERRα 的抑制进一步增强了 ACY1215 增加的 OS 耐药细胞的化疗敏感性。从机制上讲，K129 乙酰化是 HDAC6 调节 ERRα 蛋白水平的关键残基。总的来说，我们发现 ERRα 有助于 HDAC6 诱导的 OS 细胞的化疗耐药性。抑制 HDAC6/ERRα 轴可能是克服化疗耐药性和提高 OS 治疗效率的潜在方法。