A fundamental question in cancer biology is how metabolic changes drive the development of cancer. Although obesity has been recognized as a key factor in the development of human cancer, the underlying mechanisms that connect these two pathologies are not well understood. PTEN, a key tumor suppressor, regulates glucose and lipid metabolism. In our previous grant period we defined new classes of genes, transcribed by RNA polymerase III, which are targeted by PTEN and crucial for its function as a tumor suppressor. We also made a key discovery that loss of PTEN results in a substantial decrease in the expression of Maf1, a molecule that has proven, unexpectedly, to be a central negative regulator of transcription. PTEN regulates Maf1 expression by inhibiting activation of the PI3K signaling pathway. Our studies characterized mammalian Maf1 and showed that it directly represses select genes transcribed by RNA polymerases II and III that promote an oncogenic state. In addition, increased Maf1 expression suppresses cellular transformation. Importantly, our new results demonstrate that in cell culture, Maf1 negatively regulates lipid accumulation by repressing the expression of key enzymes necessary for lipid biosynthesis that are elevated in many human cancers. Together, these results support the ideas that Maf1 may be a critical target of PTEN, and that Maf1 is important both for its ability to regulate metabolism as well as function as a tumor suppressor. We therefore hypothesize that loss of PTEN, and resulting activation of PI3K/AKT, result in a decrease of Maf1, which alleviates the normal repression of genes involved in lipid biogenesis and growth control, leading to fatty liver disease and tumorigenesis. We plan to test this hypothesis in three aims using both molecular and biological models.
Aim 1 will identify the specific PI3K/PTEN-dependent molecular signaling events that regulate Maf1 expression.
Aim 2 will elucidate how Maf1 regulates fatty acid synthase and will identify other Maf1-regulated genes involved in lipid biosynthesis.
In Aim 3, we will establish mouse models where Maf1 expression is increased in the livers of mice deficient in PTEN. A genetic model in which Pten is deleted in the liver has been described. These mice, which have reduced Maf1 levels in the liver, develop steatosis starting at one month and liver cancer at 9-12 months of age. Importantly, the development of fatty liver disease is required for tumor formation. This mouse model will allow us to determine whether restoring Maf1 amounts to livers that are deficient for Pten prevents or delays the onset of fatty liver disease and tumorigenesis. If successful, these studies will identify a novel role for Maf1 as a central coordinator of metabolic signals and will thus provide a new molecular mechanism for the long-known association between obesity and cancer.
Our studies will continue to define novel and unexpected targets of the key tumor suppressor, PTEN. We will identify new mechanisms that control gene expression processes that are crucial for PTEN to negatively regulate lipid metabolism and tumorigenesis. Given the strong association between obesity and cancer, these studies will provide a new molecular mechanism that connects these two diseases and thereby substantially influence our understanding and treatment of these diseases.
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|Johnson, Deborah L; Stiles, Bangyan L (2016) Maf1, A New PTEN Target Linking RNA and Lipid Metabolism. Trends Endocrinol Metab 27:742-750|
|Palian, Beth M; Rohira, Aarti D; Johnson, Sandra A S et al. (2014) Maf1 is a novel target of PTEN and PI3K signaling that negatively regulates oncogenesis and lipid metabolism. PLoS Genet 10:e1004789|
|Khanna, Akshat; Johnson, Deborah L; Curran, Sean P (2014) Physiological roles for mafr-1 in reproduction and lipid homeostasis. Cell Rep 9:2180-91|
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|Zhong, Shuping; Machida, Keigo; Tsukamoto, Hide et al. (2011) Alcohol induces RNA polymerase III-dependent transcription through c-Jun by co-regulating TATA-binding protein (TBP) and Brf1 expression. J Biol Chem 286:2393-401|
|Zhong, Shuping; Johnson, Deborah L (2009) The JNKs differentially regulate RNA polymerase III transcription by coordinately modulating the expression of all TFIIIB subunits. Proc Natl Acad Sci U S A 106:12682-7|
|Woiwode, Annette; Johnson, Sandra A S; Zhong, Shuping et al. (2008) PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex. Mol Cell Biol 28:4204-14|
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