Differential roles of Sirt1 in HIF-1伪 and HIF-2伪 mediated hypoxic responses
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- 作者：Haejin Yoon ; Seung-Hyun Shin ; Dong Hoon Shin ; Yang-Sook Chun ; Jong-Wan Park
- 关键词：Ac-K ; acetylated lysine residue ; CAD ; C-terminal transactivation domain ; CBP ; CREB-binding protein ; DBD ; DNA-binding domain ; HDAC ; histone deacetylase ; HIF ; hypoxia-inducible factor ; PCAF ; p300/CBP-associated factor ; Sirt1 ; sirtuin 1
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：31 January, 2014
- 年：2014
- 卷：444
- 期：1
- 页码：36-43
- 全文大小：1058 K
文摘
Hypoxia-inducible factors 1伪 and 2伪 (HIF-1伪 and HIF-2伪) determine cancer cell fate under hypoxia. Despite the similarities of their structures, HIF-1伪 and HIF-2伪 have distinct roles in cancer growth under hypoxia, that is, HIF-1伪 induces growth arrest whereas HIF-2伪 promotes cell growth. Recently, sirtuin 1 (Sirt1) was reported to fine-tune cellular responses to hypoxia by deacetylating HIF-1伪 and HIF-2伪. Yet, the roles of Sirt1 in HIF-1伪 and HIF-2伪 functions have been controversial. We here investigated the precise roles of Sirt1 in HIF-1伪 and HIF-2伪 regulations. Immunological analyses revealed that HIF-1伪 K674 and HIF-2伪 K741 are acetylated by PCAF and CBP, respectively, but are deacetylated commonly by Sirt1. In the Gal4 reporter systems, Sirt1 was found to repress HIF-1伪 activity constantly in ten cancer cell-lines but to regulate HIF-2伪 activity cell type-dependently. Moreover, Sirt1 determined cell growth under hypoxia depending on HIF-1伪 and HIF-2伪. Under hypoxia, Sirt1 promoted cell proliferation of HepG2, in which Sirt1 differentially regulates HIF-1伪 and HIF-2伪. In contrast, such an effect of Sirt1 was not shown in HCT116, in which Sirt1 inactivates both HIF-1伪 and HIF-2伪 because conflicting actions of HIF-1伪 and HIF-2伪 on cell growth may be offset. Our results provide a better understanding of the roles of Sirt1 in HIF-mediated hypoxic responses and also a basic concept for developing anticancer strategy targeting Sirt1.