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Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13

Oncogene volume 26, pages 802–812 (2007)Cite this article

Abstract

DEC1/STRA13 is a bHLH type transcriptional regulator involved with immune regulation, hypoxia response and carcinogenesis. We recently demonstrated that STRA13 interacts with STAT3 in the transcriptional activation of STAT-dependent promoters. Here, we pursue STRA13 involvement in the JAK/STAT pathway by studying its role in STAT1 expression. First, we showed that VHL deficiency or HIF-1 activation resulted in the repression of endogenous STAT1 mediated by STRA13. We then characterized the STAT1 proximal promoter to assess its response to STRA13 by transient coexpression in a luciferase reporter assay. Using sequential truncation and site-directed mutagenesis of the STAT1 promoter with STRA13 deletion constructs, we showed that the STRA13 C-terminal trans-activation domain, which is known to bind HDAC1, mostly determines the repressive activity. Involvement of HDAC activity in STAT1 regulation was validated by TSA inhibition and chromatin immunoprecipitation (ChIP) assay. Thus, we demonstrate that STRA13-mediated repression of STAT1 transcription utilizes an HDAC1-dependent mechanism. Furthermore, we show that targets of unphosphorylated STAT1, such as antigen presenting genes and CASP1, are also repressed by hypoxia possibly through the same STRA13-mediated mechanism. Thus, the newly discovered link between HIF-1 and STAT1 reveals a previously unknown role of STRA13 in hypoxia and carcinogenesis.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

STAT1:

signal transducer and activator 1

VHL and pVHL:

von Hippel Lindau gene and protein

HIF-1:

hypoxia-inducible factor 1

GAS:

IFN-γ activating sequence

ISRE:

IFN-stimulated responsive element

TSA:

trichostatin A

MEF, mouse embryonic fibroblasts, HRE:

hypoxia-responsive element

HDAC:

histone deacetylase

ChIP:

chromatin immunoprecipitation

DFX:

desferioxamine

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Acknowledgements

This project was funded in whole or in part with Federal funds by the Intramural Research Program of the NIH, NCI, and Contract No. NO1-CO-12400. The content of the publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Authors thank Dr Bert Vogelstein for providing STRA13-deficient HaCat cells, Robert Nalewaik for technical help with experimentation, and Laura Geil for editing the manuscript.

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Authors and Affiliations

  1. Basic Research Program, SAIC-Frederick, Inc., Frederick, MD, USA

    S V Ivanov

  2. National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD, USA

    S V Ivanov, K Salnikow & M I Lerman

  3. Department of Cardiothoracic Surgery, NYU Medical Center, New York, NY, USA

    A V Ivanova

  4. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    L Bai

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Correspondence to S V Ivanov.

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Ivanov, S., Salnikow, K., Ivanova, A. et al. Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13. Oncogene 26, 802–812 (2007). https://doi.org/10.1038/sj.onc.1209842

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