PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia.
PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia.
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DOI：
10.1038/ncb3376
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发表时间：
2016-07
影响因子：
21.3
通讯作者：
Neel BG
中科院分区：
文献类型：
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作者：
Banh RS;Iorio C;Marcotte R;Xu Y;Cojocari D;Rahman AA;Pawling J;Zhang W;Sinha A;Rose CM;Isasa M;Zhang S;Wu R;Virtanen C;Hitomi T;Habu T;Sidhu SS;Koizumi A;Wilkins SE;Kislinger T;Gygi SP;Schofield CJ;Dennis JW;Wouters BG;Neel BG
肿瘤存在于低氧的微环境中，必须限制过度的氧气消耗。低氧诱导因子控制线粒体氧耗，但肿瘤如何/是否调节非线粒体氧耗(NMOC)尚不清楚。蛋白酪氨酸磷酸酶-1B(PTP1B)在Her2/Neu驱动的小鼠乳腺癌(BC)中是必需的，尽管其潜在的机制和人类的相关性尚不清楚。我们发现，PTP1B缺陷的HER2+异种移植物增加了缺氧、坏死和生长障碍。在体外，PTP1B缺乏通过α-KG依赖的双加氧酶(α-KGDDS)增加Nmoc使HER2+BC细胞对低氧敏感。烟雾病基因产物RNF213是一种E3连接酶，在HER2+BC细胞中受PTP1B负调控。RNF213基因敲除逆转了PTP1B缺乏对α-KGDDS、Nmoc和缺氧诱导的HER2+BC细胞死亡的影响，并部分恢复了肿瘤的致癌性。我们的结论是，PTP1B通过RNF213抑制α-KGDD活性和Nmoc。这种PTP1B/RNF213/α-KGDD通路对于HER2+BC以及其他恶性肿瘤在低氧肿瘤微环境中的生存至关重要。
Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-Tyrosine Phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, though the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2+ xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2+ BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The Moyamoya disease gene product RNF213 , an E3 ligase, is negatively regulated by PTP1B in HER2+ BC cells. RNF213 knockdown reverses the effects of PTP1B-deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2+ BC cells, and partially restores tumourigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2+ BC, and possibly other malignancies, in the hypoxic tumour microenvironment.