| According to the latest Chinese Cancer Epidemiology, the incidence and mortality of cancer have a continued upward trend despite the emergence of new cancer drugs. Thus, more in-depth research and cancer drug development become a very urgent issue. In the1920s, Otto Warburg discovered that the production of energy is majorly from glycolysis in cancer cell, unlike normal cells are more depended on the Tricarboxylic acid cycle (TCA cycle). With the development of metabolomics analysis, more and more metabolic disorders were found in cancer cells. Recently, the upregulated lipid synthesis was reported to have important role in cancer progression. The upregulation of glycolysis and de novo lipogenesis not only produce energy, they also provide the intermediate product in glycolysis and synthesized lipid to produce macromolecules for rapid proliferation. Moreover, the elevated glycolysis and de novo lipogenesis can modulate the important signals involved in cancer process.We demonstrated SRC-3, an important oncoprotein in bladder cancer, is involved in the regulation of glycolysis. The overexpressed SRC-3can promote bladder cancer cell line, BIU87proliferation as well as the increased expression of glycolytic genes and glycolysis. Moreover, the knockdown of SRC-3impairs glycolysis level of bladder cancer cells significantly associated with down-regulated glycolytic genes under hypoxia. Moreover, the deficiency of SRC-3can suppress bladder tumor formation in vivo and in vitro. In order to dissect the underlying molecular mechanism, we proved SRC-3interacted with hypoxia-inducible factor1a (HIF1α) through the bHLH/PAS domain at its N-terminus. The interaction recruits SRC-3binding to the promoter SRE region, and regulates the glycolytic genes expression. Blockade of glycolysis by compounds and RNA interference, which target HK-2and LDHA, eliminated SRC-3-induced bladder cancer cell proliferation capacity as well as disruption of HIF1αa by RNA interference. The immunochemistry staining and public database data analysis both confirm that SRC-3expression has positive correlation with glycolytic genes. Taken together, these data illustrate that SRC-3promotes bladder cancer proliferation through coactivation of HIFla.Because of rapidly dividing and modulation of some important proteins, cancer cell requires a lot of de novo synthesized lipids. Cancer cells upregulate de novo lipogenic genes to meet such needs. Firstly, higher lipid content was found in mice bladder cancer. Analysis of public databases found that de novo lipogenic genes are coincidently upregulated in bladder tumor as well as SRC-3, and have positive correlation with SRC-3in bladder cancer. We found that overexpression of SRC-3increases de novo lipogenic genes levels accompanied with the significantly up-regulated lipid accumulation in BIU87cells. Sphere formation assay and ALDH activity assay based flow cytometry analysis showed that SRC-3can increase bladder cancer stemness. Inhibition of de novo lipogenesis in bladder cancer can ablate SRC-3induced high cancer stemness and the higher expression of lipogenic genes in cancer stem cell subpopulation are proved that elevated lipogenesis can increase bladder cancer stemness. Furthermore, knockdown of SRC-3in UMUC-3cells decreases cancer stemness and lipid accumulation. We also demonstrated SRC-3coactivates Sterol regulatory element-binding protein-1c (SREBP-lc), a key de novo lipogenic gene transcription factor to regulate target genes. Furthermore, we also found that IKKa/β increased SRC-3coactivation through SRC-3(S857) site phosphorylation. Therefore, SRC-3mediates IKK signal and coactivates SREBP-lc to promote bladder cancer lipogenesis, and further increase bladder cancer steemness.In summary, this study found that the upregulated glycolysis and de novo lipid synthesis in bladder cancer promotes cancer cell proliferation and cancer stem cell maintenance. |
