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 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 cells were increased in Hdac10-deleted tumors compared with 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) lung adenocarcinoma cells inhibited growth of tumorspheres. The genes associated with TGFb pathway were enriched in Hdac10 KO tumor cells, and activation of TGFb signaling contributed to SOX9 induction in Hdac10 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.

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…By contrast, HDAC10 exhibits a potential TSG role by downregulating Sry-box transcription factor 9 (SOX9) in KRAS-driven lung adenocarcinoma. Furthermore, HDAC10 deficiency results in TGF-β pathway activation, leading to the induction of SOX9 and KRAS-expressing stem-like tumor growth (Li et al, 2020). Cancer-associated fibroblasts (CAFs) secrete extracellular matrix (ECM) that assists tumor progression and invasion.…”

Histone deacetylase 10, a potential epigenetic target for therapy

“…Specifically, by activating the transforming growth-factor β (TGF-β) pathway, deletion of HDAC10 promotes the expression of SOX9, which subsequently upregulates the expression of SLUG, as well as CD44. These processes contributes to the growth of lung cancer spheres via sex determining region Y box protein 9 (SOX9)-mediated stem-like properties, suggesting that HDAC10-TGF-β-SOX9-SLUG/ CD44 axis plays an essential role in lung adenocarcinoma (30). AMP-activated protein kinase (AMPK) regulates biological functions in tumors that are mediated by liver kinase B1 (LKB1), such as cell survival and transcription, via the mTOR Downloaded from http://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20210462/911205/bsr-2021-0462.pdf by guest on 24 May 2021 pathway (33).…”

“…It has been demonstrated that it can prompt cell proliferation in non-small-cell lung cancer (NSCLC) [ 29 ]. In contrast, HDAC10 suppresses cancer cell growth in other malignant tumors, including lung adenocarcinoma [ 30 ] and renal cell carcinoma (RCC) [ 31 ]. Akt is a key molecule in the PI3K-AKT pathway, and is involved in cell proliferation, survival and other key functions [ 32 ].…”

“…Specifically, by activating the transforming growth-factor β (TGF-β) pathway, deletion of HDAC10 promotes the expression of sex-determining region Y box protein 9 (SOX9), which subsequently up-regulates the expression of SLUG, as well as CD44. These processes contributes to the growth of lung cancer spheres via SOX9-mediated stem-like properties, suggesting that HDAC10-TGF-β-SOX9-SLUG/CD44 axis plays an essential role in lung adenocarcinoma [ 30 ].…”

Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer

“…Importantly, HDAC2-deficient colon cancer cells are highly refractory to the apoptosis induced by HDAC inhibitors. Aberrations in other classes of HDACs are also associated with CSC function and tumor stratification [ 55 , 57 ]. Sirtuins are a particular type of HDACs, the function of which is to influence extension of lifespan (longevity).…”