In hypoxic regions of malignant solid tumors, cancer cells acquire resistance to conventional therapies, such as chemotherapy and radiotherapy, causing poor prognosis in patients with cancer. It is widely recognized that some of the key genes behind this are hypoxia-inducible transcription factors, e.g., hypoxia-inducible factor 1 (HIF-1). Since HIF-1 activity is suppressed by two representative 2-oxoglutarate-dependent dioxygenases (2-OGDDs), PHDs (prolyl-4-hydroxylases), and FIH-1 (factor inhibiting hypoxia-inducible factor 1), the inactivation of 2-OGDD has been associated with cancer therapy resistance by the activation of HIF-1. Recent studies have also revealed the importance of hypoxia-responsive mechanisms independent of HIF-1 and its isoforms (collectively, HIFs). In this article, we collate the accumulated knowledge of HIF-1-dependent and independent mechanisms responsible for resistance of hypoxic cancer cells to anticancer drugs and briefly discuss the interplay between hypoxia responses, like EMT and UPR, and chemoresistance. In addition, we introduce a novel HIF-independent mechanism, which is epigenetically mediated by an acetylated histone reader protein, ATAD2, which we recently clarified.
在恶性实体肿瘤的缺氧区域，癌细胞对化疗和放疗等常规疗法产生抵抗性，导致癌症患者预后不良。学界普遍认为，缺氧诱导转录因子是这一现象背后的关键基因，例如缺氧诱导因子1（HIF-1）。由于HIF-1活性受到两种典型的2-酮戊二酸依赖性双加氧酶（2-OGDD）——脯氨酰-4-羟化酶（PHDs）和缺氧诱导因子抑制因子1（FIH-1）的抑制，2-OGDD的失活通过激活HIF-1与癌症治疗抵抗性相关联。近期研究还揭示了不依赖于HIF-1及其异构体（统称为HIFs）的缺氧响应机制的重要性。本文系统梳理了导致缺氧癌细胞对抗癌药物产生抵抗性的HIF-1依赖性与非依赖性机制的研究进展，并简要探讨了上皮间质转化（EMT）、未折叠蛋白反应（UPR）等缺氧响应与化疗耐药性之间的相互作用。此外，我们介绍了一种新型非HIF依赖性机制——该机制由乙酰化组蛋白阅读蛋白ATAD2表观遗传介导，这是我们团队近期阐明的重要发现。
肿瘤(癌症)患者之家