Hypoxia-inducible factor-2 alpha up-regulates CD70 under hypoxia and enhances anchorage-independent growth and aggressiveness in cancer cells

Abstract

Hypoxia-inducible factors (HIFs) facilitate cellular adaptation to environmental stress such as low oxygen conditions (hypoxia) and consequently promote tumor growth. While HIF-1? functions in cancer progression have been increasingly recognized, the contribution of HIF-2? remains widely unclear despite accumulating reports showing its overexpression in cancer cells. Here, we report that HIF-2? upregulates the expression of CD70, a cancer-related surface antigen that improves anchorage-independent growth in cancer cells and is associated with poor clinical prognosis, which can be induced via epigenetic modifications mediated by DNMT1. The ablation of CD70 by RNAi led to decreased colony forming efficiency in soft agar. Most strikingly, we identified the emergence of CD70-expressing cells derived from CD70-negative cell lines upon prolonged hypoxia exposure or DNMT1 inhibition, both of which significantly reduced CpG-nucleotide methylations within CD70 promoter region. Interestingly, DNMT1 expression was decreased under hypoxia, which was rescued by HIF-2? knockdown. In addition, the expression of CD70 and colony forming efficiency in soft agar were decreased by knockdown of HIF-2?. These findings indicate that CD70 expression and an aggressive phenotype of cancer cells is driven under hypoxic conditions and mediated by HIF-2? functions and epigenetic modifications. This provides additional insights into the role of HIF-2? in coordinated regulation of stem-like functions and epigenetics that are important for cancer progression and may www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 27), pp: 19123-19135 present additional targets for the development of novel combinatorial therapeutics. � Kitajima et al.