RIP140 inhibits glycolysis-dependent proliferation of breast cancer cells by regulating GLUT3 expression through transcriptional crosstalk between hypoxia induced factor and p53

Abstract

Glycolysis is essential to support cancer cell proliferation, even in the presence of oxygen. The transcriptional co-regulator RIP140 represses the activity of transcription factors that drive cell proliferation and metabolism and plays a role in mammary tumorigenesis. Here we use cell proliferation and metabolic assays to demonstrate that RIP140-deficiency causes a glycolysis-dependent increase in breast tumor growth. We further demonstrate that RIP140 reduces the transcription of the glucose transporter GLUT3 gene, by inhibiting the transcriptional activity of hypoxia inducible factor HIF-2α in cooperation with p53. Interestingly, RIP140 expression was significantly associated with good prognosis only for breast cancer patients with tumors expressing low GLUT3, low HIF-2α and high p53, thus confirming the mechanism of RIP140 anti-tumor activity provided by our experimental data. Overall, our work establishes RIP140 as a critical modulator of the p53/HIF cross-talk to inhibit breast cancer cell glycolysis and proliferation.

The Transcription Coregulator RIP140 Inhibits Cancer Cell Proliferation by Targeting the Pentose Phosphate Pathway

“…Our previous study revealed an interaction between RIP140 and the hypoxia-inducible factors (HIFs) [14], also known to regulate G6PD expression [24]. Of note, hypoxia-induced G6PD expression was abolished in RIPKO MEFs (Supplementary Figure S5B), suggesting that HIF-RIP140 interplay may be involved in the regulation of G6PD by hypoxia.…”

“…However, its role in cancer metabolism remains poorly described. Our previous work has shown that RIP140 impinges breast cancer cell proliferation by blocking glycolysis through the inhibition of the glucose transporter GLUT3 expression [14].…”

“…We previously described that RIP140 deficiency resulted in a cell growth increase [9,13,14]. We then tested whether G6PD was required by RIP140-deficient cells to proliferate at a higher rate.…”

“…On the other hand, low RIP140 expression is associated with basal-like breast cancer 2 of 12 subtypes [9]. Ambivalent effects of RIP140 on breast tumor cell proliferation have been reported with both positive [10][11][12] and negative [9,13,14] effects.…”

“…Interestingly, our recent work showed that RIP140 inhibits glucose-dependent proliferation of breast cancer cells by blocking glycolysis [14]. We then wondered whether RIP140 could also be involved in the transcriptional regulation of PPP genes in breast cancer.…”