HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis.
HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation. A452 blocked HDAC6 nuclear localization, resulting in increased levels of acetylated p53 at Lys381/382. HDAC6 bound to the C-terminal region of p53 via its deacetylase domain. A452 disrupted the HDAC6-Hsp90 chaperone machinery via Hsp90 acetylation and degradation. Furthermore, it chemosensitized cancer cells to the Hsp90 inhibitor 17-AAG. Overall, silencing of HDAC6 showed similar effects. These findings suggest that the anticancer action of HDAC6 inhibitors requires p53 and Hsp90 and targeting of HDAC6 may represent a new therapeutic strategy for cancers regardless of p53's mutation status.
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
Hyun-Wook
HW
Ryu
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
Dong-Hee
DH
Shin
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
Dong Hoon
DH
Lee
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
Junjeong
J
Choi
Department of Biotechnology, Department of Biomedical Sciences, Yonsei University, Seoul, 03722, Republic of Korea.
Gyoonhee
G
Han
Department of Surgery, College of Medicine, Yonsei University, Seoul, 03722, Republic of Korea.
Kang Young
KY
Lee
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea. Electronic address: soheekwon@yonsei.ac.kr.
So Hee
SH
Kwon
D017209:Apoptosis; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008239:Lysine; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D016159:Tumor Suppressor Protein p53; D006655:Histone Deacetylases; D008239:Lysine
Apoptosis; HDAC6-selective inhibitor; Histone deacetylase 6; Hsp90; p53