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J. Biol. Chem., Vol. 281, Issue 5, 2451-2459, February 3, 2006

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HSF1 Down-regulates XAF1 through Transcriptional Regulation^*

Jide Wang, Hua He, Lifen Yu, Harry Hua-xiang Xia, Marie C. M. Lin^¶, Qing Gu, Ming Li^¶, Bing Zou, Xiaomeng An^¶, Bo Jiang, Hsiang-Fu Kung^¶, and Benjamin C. Y. Wong¹

From the Institute for Digestive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou and the Department of Medicine and ^¶Institute of Molecular Biology, University of Hong Kong, Hong Kong, China

Studies have indicated the role of HSF1 (heat-shock transcription factor 1) in repressing the transcription of some nonheat shock genes. XAF1 (XIAP-associated factor 1) was an inhibitor of apoptosis-interacting protein with the effect of antagonizing the cytoprotective role of XIAP. XAF1 expression was lower in gastrointestinal cancers than in normal tissues with the mechanism unclear. Here we showed that gastrointestinal cancer tissues expressed higher levels of HSF1 than matched normal tissues. The expression of XAF1 and HSF1 was negatively correlated in gastrointestinal cancer cell lines. Stress stimuli, including heat, hypo-osmolarity, and H₂O₂, significantly suppressed the expression of XAF1, whereas the alteration of HSF1 expression negatively correlated with XAF1 expression. We cloned varying lengths of the 5'-flanking region of the XAF1 gene into luciferase reporter vectors, and we evaluated their promoter activities. A transcription silencer was found between the –592- and –1414-nucleotide region that was rich in nGAAn/nT-TCn elements (where n indicates G, A, T, or C). A high affinity and functional HSF1-binding element within the –862/–821-nucleotide region was determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Inactivation of this "heat-shock element" by either site-directed mutation or an HSF1 inhibitor, pifithrin-, restored the promoter activity of the silencer structure. Moreover, pretreatment with antioxidants suppressed HSF1 binding activity and increased the transcriptional activity and expression of XAF1. These findings suggested that endogenous stress pressure in cancer cells sustained the high level expression of HSF1 and subsequently suppressed XAF1 expression, implicating the synergized effect of two anti-apoptotic protein families, HSP and inhibitors of apoptosis, in cytoprotection under stress circumstances.

Received for publication, May 31, 2005 , and in revised form, October 26, 2005.

^* This work was supported by the Simon K. Y. Lee Gastroenterology Research Fund, Queen Mary Hospital, and the Gastroenterological Research Fund, University of Hong Kong. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. Tel.: 852-2855-4541; Fax: 852-2872-5828; E-mail: bcywong{at}hku.hk.

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