Department of Respiratory and Critical Care Medicine, Xi'an Central Hospital, The Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, 710004, China.
Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710048, China; Bioinspired Engineering and Biomechanics Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710048, China.
Pulm Pharmacol Ther. 2023 Dec;83:102250. doi: 10.1016/j.pupt.2023.102250. Epub 2023 Aug 30.
HDAC10 has been reported to be associated with poor prognosis in patients with non-small cell lung cancer (NSCLC), however, the regulatory role and mechanisms of HDAC10 in NSCLC have not been investigated. In this study, we found that HDAC10 was increased in NSCLC patients and cell lines. And high expression of HDAC10 is linked to poor survival in NSCLC patients. The results showed that knockdown of HDAC10 triggered DNA damage, S-phase arrest, and proliferation inhibition in A549 and H1299 cells. In addition, knockdown of HDAC10 promoted cell ferroptosis by enhancing ROS, MDA and Fe levels. Mechanistically, HDAC10 knockdown reduced SP1 expression and elevated the acetylation level of SP1, which inhibited the binding of SP1 to the promoter of POLE2, resulting in reduced POLE2 expression. Overexpression of SP1 or POLE2 partially reversed the effects of HDAC10 deletion on NSCLC cell proliferation and ferroptosis. In conclusion, knockdown of HDAC10 inhibited the proliferation of NSCLC cells and promoted their ferroptosis by regulating the SP1/POLE2 axis. HDAC10 might be a promising target for the treatment of NSCLC.
组蛋白去乙酰化酶 10（HDAC10）已被报道与非小细胞肺癌（NSCLC）患者的预后不良相关，但 HDAC10 在 NSCLC 中的调控作用和机制尚未得到研究。在本研究中，我们发现 HDAC10 在 NSCLC 患者和细胞系中表达增加。并且 HDAC10 的高表达与 NSCLC 患者的生存不良相关。结果表明，HDAC10 的敲低可触发 A549 和 H1299 细胞中的 DNA 损伤、S 期阻滞和增殖抑制。此外，HDAC10 的敲低通过增强 ROS、MDA 和 Fe 水平促进细胞铁死亡。在机制上，HDAC10 的敲低降低了 SP1 的表达并提高了 SP1 的乙酰化水平，从而抑制了 SP1 与 POLE2 启动子的结合，导致 POLE2 表达减少。SP1 或 POLE2 的过表达部分逆转了 HDAC10 缺失对 NSCLC 细胞增殖和铁死亡的影响。总之，HDAC10 的敲低通过调节 SP1/POLE2 轴抑制 NSCLC 细胞的增殖并促进其铁死亡。HDAC10 可能是治疗 NSCLC 的一个有前途的靶点。
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