title: 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.
authors.affiliation: Department of Pathology, College of Medicine and Functional RNomics Research Center, The Catholic University of Korea, Banpo-dong, Seocho-gu, Seoul, Korea.
authors.forename: Kwang Hwa
authors.initials: KH
authors.lastname: Jung
authors.forename: Ji Heon
authors.initials: JH
authors.lastname: Noh
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Kim
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Eun
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Bae
authors.forename: Hong Jian
authors.initials: HJ
authors.lastname: Xie
authors.forename: Young Gyoon
authors.initials: YG
authors.lastname: Chang
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Kim
authors.forename: Hanna
authors.initials: H
authors.lastname: Park
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C503688:CCNE2 protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D050684:E2F Transcription Factors; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019938:Cyclin D1; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D056464:Histone Deacetylase 2