Hypoxia-inducible factor 2 (HIF-2) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity

Abstract

Colorectal cancer (CRC) is the third-leading cause of cancer mortality in the United States and other industrialized countries. A hypoxic microenvironment is a hallmark for solid tumors. The hypoxia-induced signal transduction is transcrip-tionally mediated by hypoxia-inducible factor (HIF). Three major HIF isoforms, HIF-1, HIF-2, and HIF-3, are present in the intestine. Our previous work demonstrates that HIF-2 is essential for CRC growth and progression. However, the mechanisms mediating cell proliferation after hypoxia or HIF-2 activation in CRC are unclear. Data mining of RNA-Seq experiments with mouse models of intestinal HIF-2 or Yes-associated protein 1 (YAP1) overexpression indicates a significant overlap of genes in these conditions. YAP1 is a transcriptional co-activator in the Hippo signaling pathway, and YAP1-induced transcriptional responses are essential in cancer cell proliferation. Here, we report that HIF-2 robustly increases YAP1 expression and activity in CRC-derived cell lines and in mouse models. The potentiation of YAP1 activity by HIF-2 was not via canonical signaling mechanisms such as Src (non-receptor tyrosine kinase), PI3K, ERK, or MAPK pathways. Moreover, we detected no direct interaction of HIF-2 with YAP1. Of note, YAP1 activation was critical for cancer cell growth under hypoxia. Our findings indicate that HIF-2 increases cancer cell growth by up-regulating YAP1 activity, suggesting that this pathway might be targeted in potential anti-cancer approaches for treating CRC patients.