HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins

Abstract

Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses, and is often significantly overexpressed in solid tumors, but little is known of its role in human lung cancer. In this study, we demonstrated the aberrant expression of HDAC2 in lung cancer tissues and investigated oncogenic properties of HDAC2 in human lung cancer cell lines. HDAC2 inactivation resulted in regression of tumor cell growth and activation of cellular apoptosis via p53 and Bax activation and Bcl2 suppression. In cell cycle regulation, HDAC2 inactivation caused induction of p21WAF1/CIP1 expression, and simultaneously suppressed the expressions of cyclin E2, cyclin D1, and CDK2, respectively. Consequently, this led to the hypophosphorylation of pRb protein in G1/S transition and thereby inactivated E2F/DP1 target gene transcriptions of A549 cells. In addition, we demonstrated that HDAC2 directly regulated p21WAF1/CIP1 expression in a p53-independent manner. However, HDAC1 was not related to p21WAF1/CIP1 expression and tumorigenesis of lung cancer. Lastly, we observed that sustained-suppression of HDAC2 in A549 lung cancer cells attenuated in vitro tumorigenic properties and in vivo tumor growth of the mouse xenograft model. Taken together, we suggest that the aberrant regulation of HDAC2 and its epigenetic regulation of gene transcription in apoptosis and cell cycle components play an important role in the development of lung cancer.

SKLB316, a novel small-molecule inhibitor of cell-cycle progression, induces G2/M phase arrest and apoptosis in vitro and inhibits tumor growth in vivo

“…Previous researches showed that HDACs including HDAC 2 are associated with the stability of proteins that regulate cell cycle, including some cyclins such as cyclin A/E/D1, CDKs like CDK2 and other cell cycle associated components. Thus it could regulate cancer cell growth arrest and apoptosis, and agents that regulate HDAC 2 could exhibit anticancer activities [43][44][45]. So we suggest that HDAC, especially HDAC 2, may be the direct target of SKLB316.…”

Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD

“…COPD has been shown to increase the risk for developing lung cancer (143). Overexpression of HDAC2 confers oncogenic potential to human lung cancer cells (49). Thus further study is required to resolve this controversy by differentiating HDAC2 regulation and its dependent epigenetic changes in senescence during the development of COPD and lung cancer.…”

Histone deacetylase 3 promotes pancreatic cancer cell proliferation, invasion and increases drug-resistance through histone modification of P27, P53 and Bax

“…Valproic acid and TSA affect acetylation status of p53 and induce apoptosis in ERG-positive prostate cancer cells (26). In human lung cancer cell lines, HDAC inactivation results in the induction of apoptosis via p53 and Bax activation (27). P27, which inhibits CDK4-and CDK2-containing complexes, was induced by vorinostat and/or TSA, in leukemia cells (28) and breast cancer cells (29).…”