TMET-03. ONCOGENIC STAT3 PROMOTES TUMOR GROWTH VIA STIMULATION THE SCAP- AND SREBP-1-REGULATED LIPOGENIC PATHWAY

Abstract Augmented lipogenesis is a hallmark of cancer. In addition, signal transducer and activator of transcription 3 (STAT3) is aberrantly activated and associated with poor prognosis in multiple cancers. Whether oncogenic STAT3 has an intrinsic and causal link to lipogenesis in cancer remains unclear. Here, we show that inhibition of STAT3 significantly alters the lipid profile of tumor cells, including free fatty acids and derived membrane structural phospholipids (phosphatidic acid, phosphatidylinositol, phosphatidylserine and sphingomyelin), this change results in cell death which could be rescued by lipids (oleic acid and palmitoleic acid) supplementation, while suppressing the gene and protein expression of major mediators of the lipogenic pathway including sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-1, fatty acid synthase and stearoyl-CoA desaturase 1. Furthermore, we show that STAT3 binds the promoter of SCAP, SREBP-1a and SREBP-1c, to promote their transcription in tumor cells. Finally, targeting STAT3 in a xenograft mouse model blocked glioblastoma growth and lipogenic enzyme expression. Our study reveals a novel regulatory pathway of STAT3-SCAP/SREBP-1 involved in tumor growth in vitro and in vivo, connecting STAT3 signaling with SCAP- and SREBP-1-mediated lipogenesis.