HDAC10 Regulates Cancer Stem-Like Cell Properties in KRAS-Driven Lung Adenocarcinoma

Abstract

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 <i>Kras</i> allele. <i>Hdac10</i> 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 cells were increased in <i>Hdac10</i>-deleted tumors compared with <i>Hdac10</i> wild-type tumors. HDAC10 regulated the stem-like properties of KRAS-expressing tumor cells by targeting SOX9. Expression of SOX9 was significantly increased in <i>Hdac10</i>-deleted tumor cells and depletion of SOX9 in <i>Hdac10</i> knockout (KO) lung adenocarcinoma cells inhibited growth of tumorspheres. The genes associated with TGFβ pathway were enriched in <i>Hdac10</i> KO tumor cells, and activation of TGFβ signaling contributed to SOX9 induction in <i>Hdac10</i> KO lung adenocarcinoma cells. Overall, our study evaluates the functions and mechanisms of action of HDAC10 in lung carcinogenesis that will inform the rationale for targeting its related regulatory signaling as an anticancer strategy. SIGNIFICANCE: These findings linking HDAC10 and lung tumorigenesis identify potential novel strategies for targeting HDAC10 as a treatment for lung cancer.