Knockdown of HDAC10 inhibits POLE2-mediated DNA damage repair in NSCLC cells by increasing SP1 acetylation levels.

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.