HIF-1α and TAZ serve as reciprocal co-activators in human breast cancer cells

// Lisha Xiang 1,2,3 , Daniele M. Gilkes 2,3 , Hongxia Hu 2,3 , Weibo Luo 2,3 , John W. Bullen 2,3 , Houjie Liang 1 and Gregg L. Semenza 2,3,4 1 Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China 2 Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence to: Gregg L. Semenza, email: // Keywords : breast cancer progression, hypoxia-inducible factor 1, MDA-MB-231 cells, MCF-7 cells Received : May 05, 2015 Accepted : May 05, 2015 Published : May 19, 2015 Abstract Hypoxia-inducible factor 1α (HIF-1α) expression is a hallmark of intratumoral hypoxia that is associated with breast cancer metastasis and patient mortality. Previously, we demonstrated that HIF-1 stimulates the expression and activity of TAZ, which is a transcriptional effector of the Hippo signaling pathway, by increasing TAZ synthesis and nuclear localization. Here, we report that direct protein-protein interaction between HIF-1α and TAZ has reciprocal effects: HIF-1α stimulates transactivation mediated by TAZ and TAZ stimulates transactivation mediated by HIF-1α. Inhibition of TAZ expression impairs the hypoxic induction of HIF-1 target genes, such as PDK1, LDHA, BNIP3 and P4HA2 in response to hypoxia, whereas inhibition of HIF-1α expression impairs TAZ-mediated transactivation of the CTGF promoter. Taken together, these results complement our previous findings and establish bidirectional crosstalk between HIF-1α and TAZ that increases their transcriptional activities in hypoxic cells.