Editors' ChoiceCancer

RIGging the Therapeutic Response

Sci. Signal.  21 Jan 2014:
Vol. 7, Issue 309, pp. ec22
DOI: 10.1126/scisignal.2005084

Hepatocellular carcinoma (HCC) is prevalent in men and has few therapeutic options. Only some HCC patients respond to interferon α (IFNα) therapy, which inhibits cell proliferation by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Hou et al. found that the retinoic acid–inducible gene-1 (RIG-1) protein is critical to the response to IFNα in HCC. cDNA microarray analysis of normal liver and tumor tissues from HCC patients indicated that RIG-1 was the interferon-inducible gene with the most significantly decreased expression in HCC tissue at a greater frequency in men than in women. Chromatin analysis identified decreased histone H3 Lys4 (H3K4) methylation (an epigenetic mark that is associated with transcriptional activation) but increased H3K9 and H3K27 methylation (epigenetic marks that are associated with transcriptional repression) in patient HCC tissue at a greater frequency in men than women. Experimental mouse models of HCC also showed gender disparity in HCC incidence, and the decreased incidence of HCC in female mice was nearly abolished by RIG-1 knockout. In HCC patients, low RIG-1 expression correlated with poor disease-free and overall survival as well as decreased response to IFNα therapy. RIG-1 deficiency in HCC cells suppressed IFNα-induced apoptosis in culture and in xenografts and inhibited IFNα-induced gene expression in culture. RIG-1 and STAT1 coimmunoprecipitated after IFNα treatment, and RIG-1 deficiency in HCC cells inhibited the phosphorylation and nuclear translocation of STAT1 but did not further suppress gene expression in STAT1-deficient HCC cells, indicating that RIG-1 functions upstream of STAT1. A coimmunoprecipitation screen in IFNα-treated liver tissue of JAK/STAT inhibitors revealed that STAT1 binding to Src homology region 2 domain–containing phosphatase-1 (SHP1) was enhanced by RIG-1 deficiency. Both the CARD domain of RIG-1 and the SH2 domain of SHP1 bound to the transactivation domain of STAT1, and SHP1 deficiency restored IFNα-induced gene expression in RIG-1–deficient cells. Together, the findings indicate that RIG-1 may disrupt the interaction between STAT1 and its inhibitor SHP1 to mediate the response to IFNα and that RIG-1 abundance may predict the response of HCC patients to IFNα therapy.

J. Hou, Y. Zhou, Y. Zheng, J. Fan, W. Zhou, I.O.L. Ng, H. Sun, L. Qin, S. Qiu, J.M.F. Lee, C.-M. Lo, K. Man, Y. Yang, Y. Yang, Y. Yang, Q. Zhang, X. Zhu, N. Li, Z. Wang, G. Ding, S.-M. Zhuang, L. Zheng, X. Luo, Y. Xie, A. Liang, Z. Wang, M. Zhang, Q. Xia, T. Liang, Y. Yu, X. Cao, Hepatic RIG-1 predicts survival and interferon-α therapeutic response in hepatocellular carcinoma. Cancer Cell 25, 49–63 (2014). [PubMed]

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