Wei Yu, Zhang Dian, Shi He, Qian Husun, Chen Hongling, Zeng Qian, Jin Fangfang, Ye Yan, Ou Zuli, Guo Minkang, Guo Bianqin, Chen Tingmei
Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
Genes Dis. 2023 Jul 15;11(4):101041. doi: 10.1016/j.gendis.2023.06.013. eCollection 2024 Jul.
Pyruvate dehydrogenase kinase 1 (PDK1) phosphorylates the pyruvate dehydrogenase complex, which inhibits its activity. Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis, which plays an important role in tumor progression. This study aims to elucidate how PDK1 promotes breast cancer progression. We found that PDK1 was highly expressed in breast cancer tissues, and PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α (hypoxia-inducible factor 1α) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α. The HIF-1α protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1α transcriptional activity. In summary, PDK1 enhances HIF-1α protein stability by phosphorylating HIF-1α at Ser451 and promotes HIF-1α transcriptional activity by enhancing the binding of HIF-1α to P300. PDK1 and HIF-1α form a positive feedback loop to promote breast cancer progression.
丙酮酸脱氢酶激酶1（PDK1）可使丙酮酸脱氢酶复合体磷酸化，从而抑制其活性。抑制丙酮酸脱氢酶复合体可抑制三羧酸循环以及肿瘤细胞代谢重编程为糖酵解，而这在肿瘤进展中起着重要作用。本研究旨在阐明PDK1如何促进乳腺癌进展。我们发现PDK1在乳腺癌组织中高表达，敲低PDK1可降低乳腺癌细胞的增殖、迁移和致瘤性，并抑制缺氧诱导因子1α（HIF-1α）信号通路。进一步研究表明，PDK1通过降低HIF-1α的泛素化水平来促进其蛋白稳定性。HIF-1α蛋白水平依赖于PDK1激酶活性。此外，在野生型乳腺癌细胞中检测到HIF-1α丝氨酸451位点磷酸化，而在PDK1基因敲除的乳腺癌细胞中未检测到。HIF-1α丝氨酸451位点的磷酸化通过抑制HIF-1α与冯希佩尔-林道蛋白和脯氨酰羟化酶结构域的相互作用来稳定其蛋白水平。我们还发现PDK1增强了HIF-1α的转录活性。总之，PDK1通过在丝氨酸451位点磷酸化HIF-1α增强其蛋白稳定性，并通过增强HIF-1α与P300的结合来促进HIF-1α转录活性。PDK1和HIF-1α形成正反馈环以促进乳腺癌进展。
