PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1a

作者全名：Wei, Yu; Zhang, Dian; Shi, He; Qian, Husun; Chen, Hongling; Zeng, Qian; Jin, Fangfang; Ye, Yan; Ou, Zuli; Guo, Minkang; Guo, Bianqin; Chen, Tingmei

作者地址：[Wei, Yu; Zhang, Dian; Shi, He; Qian, Husun; Chen, Hongling; Zeng, Qian; Jin, Fangfang; Ye, Yan; Ou, Zuli; Guo, Minkang; Chen, Tingmei] Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Minist Educ, Chongqing 400016, Peoples R China; [Guo, Bianqin] Chongqing Univ Canc Hosp, Chongqing Key Lab Translat Res Canc Metastasis & I, Chongqing 400030, Peoples R China

通信作者：Chen, TM (通讯作者)，Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Minist Educ, Chongqing 400016, Peoples R China.; Guo, BQ (通讯作者)，Chongqing Univ Canc Hosp, Chongqing Key Lab Translat Res Canc Metastasis & I, Chongqing 400030, Peoples R China.

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001219418600001

JCR分区：Q1

影响因子：6.9

年份：2024

卷号：11

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：Breast cancer; HIF-1a; PDK1; Protein phosphorylation; Transcriptional activity

摘要：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-1a (hypoxia-inducible factor 1a) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1a by reducing the level of ubiquitination of HIF-1a. The HIF-1a protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1a phosphorylation at serine 451 was detected in wild -type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1a at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1a with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1a transcriptional activity. In summary, PDK1 enhances HIF-1a protein stability by phosphorylating HIF-1a at Ser451 and promotes HIF-1a transcriptional activity by enhancing the binding of HIF-1a to P300. PDK1 and HIF-1a form a positive feedback loop to promote breast cancer progression.

基金机构：National Nat- ural Science Foundation of China [82073255]; Foundation of Chongqing Municipal Education Commission (China) [HZ2021006]

基金资助正文：This work was supported by grants from the National Nat- ural Science Foundation of China (No. 82073255) and the Foundation of Chongqing Municipal Education Commission (China) (No. HZ2021006) .