title: Selective inhibition of histone deacetylase 2 induces p53-dependent survivin downregulation through MDM2 proteasomal degradation.
abstract: In the present study, we found that selective inhibition of histone deacetylase 2 (HDAC2) with small inhibitory RNA (siRNA) induced survivin downregulation in a p53-dependent manner. Interestingly, suberoylanilide hydroxamic acid (SAHA) or knockdown of HDAC2 induced downregulation of Mdm2, a negative regulator of p53, at the protein level. SAHA and/or HDAC2 siRNA increased Mdm2 ubiquitination, and MG132, an inhibitor of proteosome function, prevented HDAC2 inhibition-induced degradation of Mdm2. Clinically, the mRNA levels of HDAC2 and survivin were prominently overexpressed in lung cancer patients compared to normal lung tissues. Silencing of HDAC2 enhanced the cell death caused by ionizing radiation in lung cancer cells. Collectively, our results indicate that selective inhibition of HDAC2 causes survivin downregulation through activation of p53, which is mediated by downregulation of Mdm2. They further suggest that HDAC2 may exert a dominant effect on lung cancer cell survival by sustaining Mdm2-survivin levels.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: Sung-Keum
authors.initials: SK
authors.lastname: Seo
authors.affiliation: Human Resource Biobank, Cheil General Hospital, Catholic Kwandong University College of Medicine, Jung-gu, Seoul, Republic of Korea.
authors.forename: Chang-Sun
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul, Republic of Korea.
authors.forename: Tae-Boo
authors.initials: TB
authors.lastname: Choe
authors.affiliation: Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Yi
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Yonsei University, Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Hyun-Gyu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, College of Medicine, Yonsei University, Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Sang Taek
authors.initials: ST
authors.lastname: Oh
authors.affiliation: Department of Radiation Oncology, College of Medicine, Yonsei University, Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000077022:Survivin; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C107489:BIRC5 protein, human; D056572:Histone Deacetylase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D061988:Proteasome Inhibitors; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: HDAC2; Mdm2; lung cancer; p53; survivin