Department of Pathology, College of Medicine and Functional RNomics Research Center, The Catholic University of Korea, Banpo-dong, Seocho-gu, Seoul, Korea.
J Cell Biochem. 2012 Jun;113(6):2167-77. doi: 10.1002/jcb.24090.
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.
组蛋白去乙酰化酶 2（HDAC2）对于胚胎发育至关重要，影响与免疫反应相关的细胞因子信号，并且在实体瘤中通常过度表达，但人们对其在人类肺癌中的作用知之甚少。在这项研究中，我们证明了 HDAC2 在肺癌组织中的异常表达，并研究了 HDAC2 在人类肺癌细胞系中的致癌特性。HDAC2 的失活导致肿瘤细胞生长的消退和通过 p53 和 Bax 激活以及 Bcl2 抑制的细胞凋亡的激活。在细胞周期调控中，HDAC2 的失活导致 p21WAF1/CIP1 的表达诱导，同时分别抑制细胞周期蛋白 E2、细胞周期蛋白 D1 和 CDK2 的表达。因此，这导致 pRb 蛋白在 G1/S 转换中的低磷酸化，从而使 A549 细胞中的 E2F/DP1 靶基因转录失活。此外，我们证明 HDAC2 以 p53 非依赖性方式直接调节 p21WAF1/CIP1 的表达。然而，HDAC1 与 p21WAF1/CIP1 的表达和肺癌的肿瘤发生无关。最后，我们观察到 A549 肺癌细胞中 HDAC2 的持续抑制减弱了小鼠异种移植模型中的体外致瘤特性和体内肿瘤生长。总之，我们认为 HDAC2 的异常调节及其在凋亡和细胞周期成分中的基因转录的表观遗传调控在肺癌的发展中起着重要作用。
