Histone deacetylase 6 modulates autophagy through HIF-1α/BNIP3 signaling in lung cancer

Histone deacetylase 6 (HDAC6) plays an important role in the development and prognosis of lung cancer. Increasing evidence suggests that HDAC6-mediated regulation of autophagy may contribute to tumor progression and therapeutic resistance. However, the precise molecular mechanisms by which HDAC6 modulates autophagic pathways in lung cancer remain incompletely understood and warrant further investigation. In this study, clinical lung cancer specimens(N = 100) were analyzed, revealing that HDAC6 expression was significantly associated with tumor stage (P = 0.012) and tumor grade (P = 0.028). High expression of HDAC6 increased the survival risk of lung cancer patients by 3.652-fold and significantly reduced the survival rate (P ≤ 0.001). Our findings further demonstrate that HDAC6 modulates autophagy by regulating the HIF-1α/BNIP3 signaling pathway through its deacetylase activity. Moreover, pharmacological inhibition of HDAC with Trichostatin A (TSA) suppressed both HDAC6 and BNIP3 expression, decreased autophagic activity, and reduced lung tumor formation in a KRAS^G12D+/P53^loxP/loxP transgenic mouse model. Collectively, these results reveal a novel HDAC6-HIF-1α-BNIP3 axis that governs autophagy in lung cancer and underscore the potential of HDAC6 as a therapeutic target for modulating autophagy and inhibiting lung tumor progression.