Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion
Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion
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DOI：
10.1038/s41467-019-10374-y
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发表时间：
2019-06-14
影响因子：
16.6
通讯作者：
Chan, Chia-Hsin
中科院分区：
文献类型：
--
作者：
Lee, Hong-Jen;Li, Chien-Feng;Chan, Chia-Hsin
已经做出了巨大的努力来靶向癌细胞的代谢依赖性以开发新的疗法。然而，糖酵解抑制剂的治疗功效是有限的，因为它们不能引起细胞死亡。己糖激酶2（HK 2）通过其线粒体定位，作为整合糖酵解激活和凋亡恢复的中心联系发挥作用。在这里，我们确定K63连接的泛素化HectH 9调节线粒体定位和功能的HK 2。通过稳定同位素示踪方法和功能代谢分析，我们表明HectH 9缺陷通过抑制HK 2阻碍肿瘤葡萄糖代谢和生长。HectH 9/HK 2通路调节癌症干细胞（CSC）扩增和CSC相关的化学抗性。组织学分析显示，HectH 9表达上调，并与前列腺癌的疾病进展相关。这项工作揭示了HectH 9是HK 2和癌症代谢的新型调节剂。靶向HectH 9代表了通过同时破坏糖酵解和诱导细胞凋亡来实现长期肿瘤缓解的有效策略。
Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.