HDAC10 Regulates Cancer Stem-like Cell Properties in KRAS-driven Lung Adenocarcinoma

Activation of oncogenic KRAS is the most common driving event in lung adenocarcinoma development. Despite the existing rationale for targeting activated KRAS and its downstream effectors, the failure of clinical trials to date indicates that the mechanism of KRAS-driven malignancy remains poorly understood. Here we report that histone deacetylase 10 (HDAC10) might function as a putative tumor suppressor in mice carrying a spontaneously activated oncogenic Kras allele. Hdac10 deletion accelerated KRAS-driven early-onset lung adenocarcinomas, increased macrophage infiltration in the tumor microenvironment, and shortened survival time in mice. Highly tumorigenic and stem-like lung adenocarcinoma (LUAD) cells were increased in Hdac10-deleted tumors compared to Hdac10 wild-type tumors. HDAC10 regulated the stem-like properties of KRAS-expressing tumor cells by targeting SOX9. Expression of SOX9 was significantly increased in Hdac10-deleted tumor cells and depletion of SOX9 in Hdac10 knockout (KO) LUAD cells inhibited growth of tumor spheres. The genes associated with TGF-β pathway were enriched in Hdac10 KO tumor cells, and activation of TGF-β signaling contributed to SOX9 induction in Hdac10 KO LUAD cells. Overall, our study evaluates the functions and mechanisms of action of HDAC10 in lung carcinogenesis which will inform the rationale for targeting its related regulatory signaling as an anticancer strategy.