Endometrial cancer is the most common gynaecological cancer of the developed world and is strongly linked to obesity. To gain a better understanding of the links between obesity and endometrial cancer development, we compared gene expression signatures from endometrial tissues obtained from equally obese women with and without cancer. This analysis showed that glucose transporter 6 (GLUT6) was upregulated 37-fold in malignant endometrium compared to normal endometrium of women without cancer . Functional studies revealed that GLUT6 is essential for endometrial cancer cell survival despite the expression of other glucose transporters . GLUT6 expression is low in normal endometrial cells and other tissues; therefore, GLUT6 represents as a potentially novel and cancer-selective therapeutic target.
There are no known inhibitors of GLUT6; therefore, we investigated its mechanism of regulation to reveal alternate means to decrease GLUT6 expression. Using a transcription factor knockdown array targeting 270 common transcription factors, we identified RelA as a positive regulator of GLUT6 gene expression. RelA, a member of the NF-κB family is a master regulator of inflammatory signalling. We demonstrated that GLUT6 gene and protein expression was increased by overexpressing constitutively active RelA and by stimulation with RelA activators including inflammatory cytokines TNFα and IL-1β. Moreover, introducing a dominant-negative RelA mutant decreased GLUT6 expression and slowed endometrial cancer cell proliferation without altering proliferation of normal endometrial cells. Overall, this study identifies RelA and inflammatory stimuli as regulators of GLUT6 expression in endometrial cells. Since obesity is a low-grade chronic inflammatory condition, these data may explain how obesity is linked to GLUT6 up-regulation and endometrial cancer.