Maf1 Is a Novel Target of PTEN and PI3K Signaling That Negatively Regulates Oncogenesis and Lipid Metabolism

Abstract

Maf1 was initially identified as a transcriptional repressor of RNA pol III-transcribed genes, yet little is known about its other potential target genes or its biological function. Here, we show that Maf1 is a key downstream target of PTEN that drives both its tumor suppressor and metabolic functions. Maf1 expression is diminished with loss of PTEN in both mouse models and human cancers. Consistent with its role as a tumor suppressor, Maf1 reduces anchorage-independent growth and tumor formation in mice. PTEN-mediated changes in Maf1 expression are mediated by PTEN acting on PI3K/AKT/FoxO1 signaling, revealing a new pathway that regulates RNA pol III-dependent genes. This regulatory event is biologically relevant as diet-induced PI3K activation reduces Maf1 expression in mouse liver. We further identify lipogenic enzymes as a new class of Maf1-regulated genes whereby Maf1 occupancy at the FASN promoter opposes SREBP1c-mediated transcription activation. Consistent with these findings, Maf1 inhibits intracellular lipid accumulation and increasing Maf1 expression in mouse liver abrogates diet-mediated induction of lipogenic enzymes and triglycerides. Together, these results establish a new biological role for Maf1 as a downstream effector of PTEN/PI3K signaling and reveal that Maf1 is a key element by which this pathway co-regulates lipid metabolism and oncogenesis.

Author Summary

Obesity is a strong risk factor for human cancers, yet the biological basis for this is unclear. In addition to aberrant growth, abnormal lipid synthesis is a hallmark of cancer cells. Our results have identified a novel role for Maf1 in suppressing both lipid biogenesis and tumor formation. Maf1 elicits these biological responses through its ability to repress genes that that synthesize lipids and regulate biosynthetic capacity. Maf1 amounts are regulated through a critical cellular pathway involving PTEN/PI3K/Akt/FoxO1, which is deregulated in many human cancers. Our results support the idea that deregulation of this pathway in cancer cells results in decreases in cellular Maf1, resulting in both abnormal growth and lipid synthesis. Thus, Maf1 represents a novel link between lipid metabolism and oncogenic transformation providing a new molecular basis for the strong association between obesity and cancer.