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STAT1-independent inhibition of cyclooxygenase-2 expression by IFNγ; a common pathway of IFNγ-mediated gene repression but not gene activation

Oncogene volume 26, pages 2071–2081 (2007)Cite this article

Abstract

Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, promotes the development of colorectal cancer, and is a key molecular target of non-steroidal anti-inflammatory drugs, compounds that reduce the relative risk of developing colon cancer. In this study, we showed that interferon γ (IFNγ) inhibits the expression of COX-2 protein in intestinal epithelial cells (IECs) through a pathway that requires Janus-activated kinase (JAK) activity. In contrast, we demonstrated that transcriptional inhibition of COX-2 by IFNβ or IFNγ occurs in cells with silenced signal transducer and activator of transcription 1 (STAT1) expression and that IFNs retained the ability to inhibit COX-2 transcription in cells with activated RasV12, in which IFNγ failed to induce STAT1. Thus, unlike the activity of JAK, STAT1 is not required for the inhibition of COX-2 expression by IFNγ. In contrast to COX-2, the activation of genes in response to IFNγ, such as interferon regulatory factor-1, was severely impaired by both STAT1 silencing and by constitutive Ras signaling. To determine whether there is a general differential requirement for STAT1 in gene activation and gene repression in response to IFNγ in intestinal cells, we performed genome-wide analysis of IFNγ target genes in an IEC line in which STAT1 expression was silenced by small interfering RNA. The results confirmed that the activation of the majority of genes by IFNγ required STAT1. In contrast, the repression of several genes, as we showed for COX-2 specifically, was largely unaffected in cells with silenced STAT1. Our results therefore demonstrate that in general gene activation by IFNγ is more sensitive to STAT1 deficiency than gene repression, and suggest that IFNγ activates and represses gene expression via distinct pathways that can be distinguished, at least in part, by their requirement for STAT1.

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Acknowledgements

We are indebted to Raymond DuBois for his generous gift of IEC-ikRas and IEC-ikRas-COX-2 5' cells. We are grateful to John Mariadason for his advice in analysing the microarray data and suggestions regarding the manuscript, and to Laura Bancroft for technical assistance. This study was supported by RO1 CA111361 (to LK), U54 CA100926 (to LA) and P30-13330 from the NCI.

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Authors and Affiliations

  1. Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY, USA

    L Klampfer, J Huang, P Kaler & L Augenlicht

  2. Research Institute, International Medical Center of Japan, Toyama, Shinjuku-ku, Tokyo, Japan

    T Sasazuki & S Shirasawa

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  1. L Klampfer
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  2. J Huang
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Correspondence to L Klampfer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Klampfer, L., Huang, J., Kaler, P. et al. STAT1-independent inhibition of cyclooxygenase-2 expression by IFNγ; a common pathway of IFNγ-mediated gene repression but not gene activation. Oncogene 26, 2071–2081 (2007). https://doi.org/10.1038/sj.onc.1210015

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