Oncogenic Control and Metabolic Outputs of the Lipogenic Transcription Factor SREBP

Abstract

The sterol regulatory element binding protein (SREBP) transcription factors have emerged as central regulators of de novo lipogenesis in the liver. However, while it is known that lipid synthesis is elevated in many cancers, much less is known about the control of lipid metabolism in this context. The goals of this dissertation were to better understand the mechanisms through which commonly mutated oncogenes and tumor suppressors promote de novo lipid synthesis, and to further define the importance of this process in cancer.

Using isogenic oncogene-expressing breast epithelial cells and breast cancer cell lines, I have identified a major mechanism through which two of the most commonly activated oncogenes in cancer promote de novo lipogenesis. In particular, I found that the expression of oncogenic PI3K or K-Ras is sufficient to stimulate de novo lipid synthesis in breast epithelial cells through the activation of mechanistic target of rapamycin complex 1 (mTORC1) and SREBP. Consistent with these findings, increased mTORC1 signaling in breast cancer patient tumor samples is associated with elevated expression of canonical SREBP targets involved in de novo lipogenesis. I further demonstrate that SREBP depletion in breast cancer cells or in oncogene-expressing epithelial cells reduces growth-factor independent proliferation.

To better understand the role of SREBP in cancer metabolism, I sought to determine whether SREBP regulates isocitrate dehydrogenase 1 (IDH1), which is both a metabolic enzyme and an oncogene. Specifically, I show that SREBP activates the expression of IDH1 across a panel of cancer cell lines from different lineages, and that IDH1 expression facilitates the flux of glutamine-derived carbons towards de novo lipid synthesis. In addition, SREBP stimulates the expression of oncogenic IDH1R132C, which is a neomorphic enzyme that produces the oncometabolite 2-hydroxyglutarate, and can regulate 2-hydroxyglutarate production in mutant-IDH1 cells.

Collectively, these studies expand our understanding of lipid metabolism in cancer and identify important roles for SREBP in cancer cell metabolism and proliferation. Our results will help guide future studies on the regulation of SREBP, the role of SREBP targets, and the production of specific lipid species in cancer, which will hopefully identify novel therapeutic targets to treat cancer patients.