Pyruvate kinase M2 interacts with nuclear sterol regulatory element-binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma
Pyruvate kinase M2 interacts with nuclear sterol regulatory element-binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma
复制标题
丙酮酸激酶 M2 与核甾醇调节元件结合蛋白 1a 相互作用，从而激活肝细胞癌中的脂肪生成和细胞增殖
DOI：
10.1074/jbc.ra117.000100
复制
发表时间：
2018-04-27
影响因子：
4.8
通讯作者：
Huang, Gang
中科院分区：
文献类型：
--
作者：
Zhao, Xiaoping;Zhao, Li;Huang, Gang
脂质代谢失调在癌细胞中很常见，但其潜在机制尚不清楚。固醇调节元件结合蛋白（SREBP）通过转录激活脂肪生成酶来刺激脂质生物合成。然而，SREBP在癌细胞中的作用和潜在的相互作用伙伴尚未完全确定。使用生物化学方法，我们发现丙酮酸激酶M2（PKM 2）通过结合nBP 1a中的氨基酸43-56与SREBP-1a（nBP 1a）的核形式发生物理相互作用。我们还发现PKM 2通过稳定nBP 1a蛋白来激活SREBP靶基因表达和脂质生物合成。使用竞争性肽抑制剂阻断SREBP-1a/PKM 2复合物的形成，我们观察到这种阻断抑制了脂肪生成基因的表达。值得注意的是，在Thr-59处的nBP 1a磷酸化增强了与PKM 2的结合并促进癌细胞生长。此外，我们表明PKM 2在体外磷酸化Thr-59。最后，在患有肝细胞癌的人类患者中，Thr-59的nBP 1a磷酸化与临床结果呈负相关。总之，我们的研究结果表明，nBP 1a/PKM 2相互作用激活癌细胞中的脂质代谢基因，SREBP-1a的Thr-59磷酸化在癌细胞增殖中起重要作用。
Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory element-binding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59 in vitro. Lastly, in human patients with hepatocellular carcinoma, nBP1a phosphorylation at Thr-59 was negatively correlated with clinical outcomes. Together, our results reveal that nBP1a/PKM2 interaction activates lipid metabolism genes in cancer cells and that Thr-59 phosphorylation of SREBP-1a plays an important role in cancer cell proliferation.