Selective inhibition of histone deacetylase 2 induces p53-dependent survivin downregulation through MDM2 proteasomal degradation
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Sung-Keum Seo1, Chang-Sun Hwang2, Tae-Boo Choe3, Seok-Il Hong4, Jae Youn Yi5, Sang-Gu Hwang1, Hyun-Gyu Lee6, Sang Taek Oh7, Yun-Han Lee7 and In-Chul Park1
1 Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea
2 Human Resource Biobank, Cheil General Hospital, Catholic Kwandong University College of Medicine, Jung-gu, Seoul, Republic of Korea
3 Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul, Republic of Korea
4 Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea
5 Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Gongneung-dong, Nowon-gu, Seoul, Republic of Korea
6 Department of Microbiology and Immunology, College of Medicine, Yonsei University, Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea
7 Department of Radiation Oncology, College of Medicine, Yonsei University, Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea
In-Chul Park, email:
Yun-Han Lee, email:
Keywords: HDAC2, Lung cancer, Mdm2, p53, Survivin
Received: July03, 2014 Accepted: December 30, 2014 Published: December 31, 2014
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.
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