Hypoxia-inducible factor-2 alpha up-regulates CD70 under hypoxia and enhances anchorage-independent growth and aggressiveness in cancer cells.
Hypoxia-inducible factor-2 alpha up-regulates CD70 under hypoxia and enhances anchorage-independent growth and aggressiveness in cancer cells.
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DOI：
10.18632/oncotarget.24919
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发表时间：
2018-04-10
期刊：
影响因子：
--
通讯作者：
Poellinger L
中科院分区：
文献类型：
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作者：
Kitajima S;Lee KL;Fujioka M;Sun W;You J;Chia GS;Wanibuchi H;Tomita S;Araki M;Kato H;Poellinger L
低氧诱导因子(HIF)促进细胞对低氧等环境应激的适应，从而促进肿瘤生长。虽然HIF-1α在肿瘤进展中的作用已得到越来越多的认识，但尽管越来越多的报告显示HIF-2α在癌细胞中过表达，但其作用仍广泛不清楚。在这里，我们报告HIF-2α上调CD70的表达，CD70是一种肿瘤相关表面抗原，促进癌细胞的锚定非依赖性生长，并与不良的临床预后相关，这可以通过DNMT1介导的表观遗传修饰来诱导。RNAi对CD70的消融导致软琼脂集落形成率下降。最引人注目的是，我们发现在长期低氧暴露或DNMT1抑制下，来自CD70阴性细胞系的CD70表达细胞的出现，这两者都显著减少了CD70启动子区的CpG-核苷酸甲基化。有趣的是，DNMT1在低氧条件下表达降低，这是由HIF-2α基因敲除所拯救的。此外，HIF-2α被敲除后，软琼脂中CD70的表达和集落形成率均降低。这些发现表明，CD70CD70的表达和癌细胞的侵袭性表型是在低氧条件下驱动的，并由HIF-2α功能和表观遗传修饰介导。这为HIF-2α在协调调节干细胞样功能和表观遗传学中的作用提供了更多的见解，这些功能和表观遗传学对癌症进展至关重要，并可能为新的组合疗法的开发提供更多的靶点。
Hypoxia-inducible factors (HIFs) facilitate cellular adaptation to environmental stress such as low oxygen conditions (hypoxia) and consequently promote tumor growth. While HIF-1α functions in cancer progression have been increasingly recognized, the contribution of HIF-2α remains widely unclear despite accumulating reports showing its overexpression in cancer cells. Here, we report that HIF-2α up-regulates 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-2α knockdown. In addition, the expression of CD70 and colony forming efficiency in soft agar were decreased by knockdown of HIF-2α. These findings indicate that CD70 expression and an aggressive phenotype of cancer cells is driven under hypoxic conditions and mediated by HIF-2α functions and epigenetic modifications. This provides additional insights into the role of HIF-2α in coordinated regulation of stem-like functions and epigenetics that are important for cancer progression and may present additional targets for the development of novel combinatorial therapeutics.