Proteolysis of a histone acetyl reader, ATAD2, induces chemoresistance of cancer cells under severe hypoxia by inhibiting cell cycle progression in S phase
Proteolysis of a histone acetyl reader, ATAD2, induces chemoresistance of cancer cells under severe hypoxia by inhibiting cell cycle progression in S phase
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DOI：
10.1016/j.canlet.2021.12.028
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发表时间：
2022-01-03
期刊：
影响因子：
9.7
通讯作者：
Harada, Hiroshi
中科院分区：
文献类型：
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作者：
Haitani, Takao;Kobayashi, Minoru;Harada, Hiroshi
癌细胞在实体瘤的缺氧区域获得化学抗性，这被认为至少部分是由于其增殖活性的降低。然而，其背后的分子机制尚未完全阐明。在这里，我们揭示了组蛋白乙酰化阅读器 ATP 酶家族 AAA 结构域包含 2 (ATAD2) 在缺氧条件下主动蛋白水解的重要性。我们发现，在严重缺氧时，O2/Fe2+/α-酮戊二酸依赖性双加氧酶的失活会触发蛋白酶体系统的 ATAD2 蛋白水解，以一种不依赖于缺氧诱导因子 (HIF) 的方式。一致的是，异种移植肿瘤组织和临床肿瘤组织中坏死周围缺氧区域的 ATAD2 表达水平显着降低。 ATAD2蛋白水解伴随着乙酰化组蛋白H3赖氨酸27数量的减少，并在严重缺氧下抑制细胞周期从早期S期到晚期S期的进展。 S 期进展的延迟会诱导化疗耐药，但 ATAD2 的过表达可阻断化疗耐药。总之，这些结果表明，严重缺氧时 ATAD2 蛋白水解会通过异染色质化和随后的 S 期进展延迟来诱导癌细胞的化疗耐药性。因此，抑制ATAD2蛋白水解有望成为克服缺氧肿瘤细胞化疗耐药性的策略。
Cancer cells acquire chemoresistance in hypoxic regions of solid tumors, which is suggested to be at least partly due to reduction of their proliferative activity. However, molecular mechanisms behind it have not been fully elucidated. Here, we revealed the importance of active proteolysis of a histone acetylation reader, ATPase family AAA domain containing 2 (ATAD2), under hypoxia. We found that inactivation of an O2/Fe2+/alpha-ketoglutaratedependent dioxygenase triggered ATAD2 proteolysis by the proteasome system upon severe hypoxia in a hypoxia-inducible factors (HIFs)-independent manner. Consistently, ATAD2 expression levels were markedly lower in perinecrotic hypoxic regions in both xenografted and clinical tumor tissues. The ATAD2 proteolysis was accompanied by a decrease in the amount of acetylated histone H3 lysine 27 and inhibited cell cycle progression from the early to late S phase under severe hypoxia. The retardation of S phase progression induced chemoresistance, which was blocked by overexpression of ATAD2. Together, these results indicate that ATAD2 proteolysis upon severe hypoxia induces chemoresistance of cancer cells through heterochromatinization and the subsequent retardation of S phase progression; therefore, inhibition of ATAD2 proteolysis is expected to be a strategy to overcome chemoresistance of hypoxic tumor cells.