| First Author | Ma X | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 41 | Pages | 17046-17056 |
| PubMed ID | 28848049 | Mgi Jnum | J:246046 |
| Mgi Id | MGI:5914305 | Doi | 10.1074/jbc.M117.805655 |
| Citation | Ma X, et al. (2017) Hypoxia-inducible factor 2alpha (HIF-2alpha) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity. J Biol Chem 292(41):17046-17056 |
| abstractText | 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 transcriptionally mediated by hypoxia-inducible factor (HIF). Three major HIF isoforms, HIF-1alpha, HIF-2alpha, and HIF-3alpha, are present in the intestine. Our previous work demonstrates that HIF-2alpha is essential for CRC growth and progression. However, the mechanisms mediating cell proliferation after hypoxia or HIF-2alpha activation in CRC are unclear. Data mining of RNA-Seq experiments with mouse models of intestinal HIF-2alpha 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-2alpha robustly increases YAP1 expression and activity in CRC-derived cell lines and in mouse models. The potentiation of YAP1 activity by HIF-2alpha 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-2alpha with YAP1. Of note, YAP1 activation was critical for cancer cell growth under hypoxia. Our findings indicate that HIF-2alpha 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. |
