Crosstalk between oncogenic signalling pathways reprograms lipid metabolism in cancer
- Cancer Metabolism Program and Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC, Australia.
Malignant transformation and tumour progression are dependent on reprogramming of cell metabolism to fulfil the unique energetic and biosynthetic needs of cancer cells. A well-recognised, but poorly understood, alteration in metabolism frequently observed in cancer cells is the activation of de novo lipogenesis. Our recent studies have focussed on the oncogenic transcriptional co-activator YAP, a master regulator of organ size and tumourigenesis. Aberrant activation of YAP is widespread in human cancers. There is little knowledge regarding mechanisms by which YAP drives tumourigenesis, in large part because a limited number of YAP target genes and effectors have been identified. We find that YAP overexpression induces de novolipogenesis in vitro and in vivo. Mechanistically, this phenomenon is dependent on the ability of YAP to induce transcriptional upregulation of serum- and glucocorticoid-regulated kinase 1 (SGK1), an effector of the oncogenic phosphoinositide 3-kinase (PI3K) pathway. Downstream of YAP, SGK1 promotes mTORC1 signalling leading to activation of the sterol regulatory element-binding proteins (SREBP1/2), master regulators of lipid metabolism. Importantly, we find that inhibition of key enzymes in the de novo lipogenesis pathway blocks the uncontrolled proliferation associated with YAP-driven transformation in vitro and in vivo. Our data reveal a mechanism of crosstalk between two important oncogenic signalling pathways and reveal a metabolic vulnerability that can be targeted to disrupt oncogenic YAP/PI3K pathway activity.