Hypoxia-inducible factor 2α (HIF-2α) 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 transcriptionally mediated by hypoxia-inducible factor (HIF). Three major HIF isoforms, HIF-1α, HIF-2α, and HIF-3α, are present in the intestine. Our previous work demonstrates that HIF-2α is essential for CRC growth and progression. However, the mechanisms mediating cell proliferation after hypoxia or HIF-2α activation in CRC are unclear. Data mining of RNA-Seq experiments with mouse models of intestinal HIF-2α 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-2α robustly increases YAP1 expression and activity in CRC-derived cell lines and in mouse models. The potentiation of YAP1 activity by HIF-2α 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-2α with YAP1. Of note, YAP1 activation was critical for cancer cell growth under hypoxia. Our findings indicate that HIF-2α 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.

Hippo Signaling Controls NLR Family Pyrin Domain Containing 3 Activation and Governs Immunoregulation of Mesenchymal Stem Cells in Mouse Liver Injury

“…Interestingly, the purinergic receptors induced cell proliferation and migration in injured tissues by regulating YAP activation, suggesting that there is a crosstalk between purinergic receptors and the Hippo‐YAP pathway. Moreover, the hypoxia‐inducible factors regulated their target genes, leading to resistance to ischemia and controlling excessive inflammation, which may interact with YAP under hypoxic conditions . These reports suggest that Hippo pathway–mediated immune regulation may be involved in multiple signaling pathways during sterile inflammatory injury.…”

Cancer stem cells and hypoxia-inducible factors (Review)

“…6) (65). The target genes participate in the proliferation, apoptosis, metabolism and invasion, as well in the and resistance of cancer cells to therapy (66)(67)(68).…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 278,279 ] Finally, HIF‐2alpha was also reported to induce YAP expression and activity in colorectal cancer cell lines and mouse models. [ 280 ] Thus, various different mechanisms have been proposed for cooperation between HIF factors and YAP, and further work is needed to explore this connection in different tumors in vivo.…”