Regulation of glucose metabolism by p62/SQSTM1 through HIF1α.
Regulation of glucose metabolism by p62/SQSTM1 through HIF1α.
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p62/SQSTM1 通过 HIF1α 调节葡萄糖代谢
DOI：
10.1242/jcs.178756
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发表时间：
2016-02-15
影响因子：
4
通讯作者：
Ye Z
中科院分区：
文献类型：
--
作者：
Chen K;Zeng J;Xiao H;Huang C;Hu J;Yao W;Yu G;Xiao W;Xu H;Ye Z
摘要信号衔接子隔离体1（SQSTM 1）/p62在肿瘤中频繁过表达，并在肿瘤发生中起着重要的调节作用。虽然已经取得了很大的进展，p62的生物学作用和负责其促肿瘤活性的相关分子机制仍然在很大程度上是未知的。在这里，我们表明p62基因敲低降低细胞生长和糖酵解基因的表达，在某种程度上取决于HIF 1 α活性在肾癌细胞。p62基因的敲低通过调节mTORC 1活性和NF-κB核转位降低HIF 1 α水平和转录活性。此外，p62直接与von Hippel-Lindau（VHL）E3连接酶复合物相互作用，以调节HIF 1 α的稳定性。在机制上，p62与VHL复合物结合并与HIF 1 α竞争。p62的表达抑制DCNL 1（也称为DCUN 1D 1）与CUL 2的相互作用并减弱CUL 2的neddylation，从而下调VHL E3连接酶复合物活性。在功能上，HIF 1 α表达是p62诱导的葡萄糖摄取、乳酸产生和软琼脂集落生长所必需的。总而言之，我们的研究结果表明，p62是HIF 1 α的关键正调节因子，而HIF 1 α是p62增强肿瘤发生的促进因子。p62是HIF 1 α的重要正调控因子，HIF 1 α是p62增强肿瘤发生的促进因子。
ABSTRACT The signaling adaptor sequestosome 1 (SQSTM1)/p62 is frequently overexpressed in tumors and plays an important role in the regulation of tumorigenesis. Although great progress has been made, biological roles of p62 and relevant molecular mechanisms responsible for its pro-tumor activity remain largely unknown. Here, we show that p62 knockdown reduces cell growth and the expression of glycolytic genes in a manner that depends on HIF1α activity in renal cancer cells. Knockdown of p62 decreases HIF1α levels and transcriptional activity by regulating mTORC1 activity and NF-κB nuclear translocation. Furthermore, p62 interacts directly with the von Hippel-Lindau (VHL) E3 ligase complex to modulate the stability of HIF1α. Mechanistically, p62 binds to the VHL complex and competes with HIF1α. Expression of p62 inhibits the interaction of DCNL1 (also known as DCUN1D1) with CUL2 and attenuates the neddylation of CUL2, and thus downregulates the VHL E3 ligase complex activity. Functionally, HIF1α expression is required for p62-induced glucose uptake, lactate production and soft agar colony growth. Taken together, our findings demonstrate that p62 is a crucial positive regulator of HIF1α, which is a facilitating factor in p62-enhanced tumorigenesis. Highlighted Article: p62 is a crucial positive regulator of HIF1α, which is a facilitating factor in p62-enhanced tumorigenesis.