Department of Urology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Breast Surgery, the Third Affiliated Hospital of Harbin Medical, University, Harbin, China.
Int J Biol Sci. 2019 Jan 1;15(2):395-403. doi: 10.7150/ijbs.27256. eCollection 2019.
Hypoxic microenvironment inside the tumor forces tumor cells to up-regulate the glycolytic pathway to maintain a sufficient energy supply for tumor growth. Activation of HIF1α under hypoxia condition is able to regulate the expression of glycolysis-related genes, and results in the proliferation and metastasis of cancer cells. However, the mechanism underlying HIF1α activation and glycolysis induction by hypoxia remains unclear. The present study is aimed to test if SENP1 regulates the glycolysis of prostate cancer cells (CaP) by improving stability of HIF1α protein. We employed qPCR and western blotting assay to analyze expression of HIF1α and SENP1. Glucose uptake assay, lactate production assay, LDH release assay and ATP production assay were utilized to evaluate cell glycolysis. The interaction between SENP1 and HIF1α was verified by co-immunoprecipitation assay. We found that hypoxia condition improves glucose uptake and lactate production to sustain sufficient ATP for cellular activity in prostatic carcinoma cells. The expression of SENP1 mRNA was significantly increased in human prostatic carcinoma cell lines after exposure to hypoxia, accompanied by the up-regulation of HIF1α. Furthermore, forced expression of SENP1 was shown to regulate the glycolysis in prostatic carcinoma cells by stabilizing HIF1α. The up-regulation of SENP1 promotes tumor cell proliferation and tumorgenesis by interacting with HIF1α which was deSUMOylated and sequentially leading to a "Warburg effect". SENP1 interacts with HIF1α to regulate glycolysis and proliferation of prostatic carcinoma cells under hypoxia condition, which provides new insights into prostatic carcinoma therapy.
肿瘤内部的缺氧微环境迫使肿瘤细胞上调糖酵解途径，以维持肿瘤生长所需的充足能量供应。缺氧条件下 HIF1α 的激活能够调节糖酵解相关基因的表达，导致癌细胞的增殖和转移。然而，缺氧诱导 HIF1α 激活和糖酵解的机制尚不清楚。本研究旨在通过提高 HIF1α 蛋白稳定性来检验 SENP1 是否调节前列腺癌细胞（CaP）的糖酵解。
我们通过 qPCR 和 Western blot 分析检测 HIF1α 和 SENP1 的表达。葡萄糖摄取实验、乳酸生成实验、LDH 释放实验和 ATP 生成实验用于评估细胞糖酵解。通过共免疫沉淀实验验证 SENP1 和 HIF1α 之间的相互作用。
我们发现，缺氧条件下提高葡萄糖摄取和乳酸生成，以维持前列腺癌细胞中细胞活动所需的充足 ATP。在暴露于缺氧后，人前列腺癌细胞系中 SENP1 的 mRNA 表达明显增加，同时 HIF1α 的表达上调。此外，SENP1 的强制表达通过稳定 HIF1α 来调节前列腺癌细胞的糖酵解。SENP1 的上调通过与 HIF1α 相互作用促进肿瘤细胞增殖和致瘤性，该作用使 HIF1α 去 SUMO 化，进而导致“Warburg 效应”。
SENP1 通过与 HIF1α 相互作用在缺氧条件下调节前列腺癌细胞的糖酵解和增殖，为前列腺癌的治疗提供了新的思路。
