Novel targets that are deregulated by loss of PTEN

描述（申请人提供）：癌症生物学的一个基本问题是代谢变化如何驱动癌症的发展。虽然肥胖已被认为是人类癌症发展的关键因素，但连接这两种病理的潜在机制尚不清楚。PTEN是一种关键的肿瘤抑制因子，调节糖脂代谢。在我们之前的资助期间，我们定义了新的基因类别，由RNA聚合酶III转录，这些基因是PTEN的靶标，对其作为肿瘤抑制因子的功能至关重要。我们也有一个重要的发现，PTEN的缺失导致Maf1的表达显著减少，这一分子已被证明是转录的中心负调控因子，出乎意料。PTEN通过抑制PI3K信号通路的激活来调节Maf1的表达。我们的研究对哺乳动物的Maf1进行了表征，并表明它直接抑制RNA聚合酶II和III转录的促进致癌状态的选择基因。此外，增加的Maf1表达抑制细胞转化。重要的是，我们的新结果表明，在细胞培养中，Maf1通过抑制在许多人类癌症中升高的脂质生物合成所必需的关键酶的表达来负性调节脂质积累。总之，这些结果支持了Maf1可能是PTEN的关键靶点的观点，并且Maf1在调节代谢和肿瘤抑制功能方面都很重要。因此，我们假设PTEN的缺失，以及由此导致的PI3K/AKT的激活，导致Maf1的减少，从而减轻了参与脂质生物发生和生长控制的基因的正常抑制，从而导致脂肪肝疾病和肿瘤发生。我们计划在三个目标中使用分子和生物学模型来验证这一假设。Aim 1将确定调节Maf1表达的PI3K/ pten依赖的特定分子信号事件。目的2将阐明Maf1如何调节脂肪酸合成酶，并将鉴定其他参与脂质生物合成的Maf1调控基因。在Aim 3中，我们将建立小鼠模型，其中在PTEN缺乏的小鼠肝脏中Maf1表达增加。已经描述了Pten在肝脏中被删除的遗传模型。这些小鼠肝脏中Maf1水平降低，在1个月大时开始出现脂肪变性，在9-12个月大时患上肝癌。重要的是，脂肪肝的发展是肿瘤形成的必要条件。该小鼠模型将使我们能够确定，在Pten缺乏的肝脏中恢复Maf1是否可以预防或延迟脂肪肝疾病和肿瘤发生的发生。如果成功，这些研究将确定Maf1作为代谢信号中心协调者的新作用，从而为肥胖和癌症之间长期已知的关联提供新的分子机制。

DESCRIPTION (provided by applicant): 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.