کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5525391 1546678 2017 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Original ArticleHDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Original ArticleHDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis
چکیده انگلیسی


- HDAC6 deacetylates p53 at lysine 381/382.
- A452 increases wild-type p53 levels by destabilizing MDM2.
- A452 decreases mutant p53 levels by inhibiting Hsp90-mutp53 complex formation.
- HDAC6 levels inversely correlate with p53 acetylation.
- A452 disrupts HDAC6-Hsp90 chaperone machinery via Hsp90 acetylation and degradation.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 391, 10 April 2017, Pages 162-171
نویسندگان
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