Maf1 is a novel target of PTEN and PI3K signaling that negatively regulates oncogenesis and lipid metabolism.
Maf1 is a novel target of PTEN and PI3K signaling that negatively regulates oncogenesis and lipid metabolism.
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MAF1是PTEN和PI3K信号的新靶标，可负调节肿瘤发生和脂质代谢。
DOI：
10.1371/journal.pgen.1004789
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发表时间：
2014-12
期刊：
影响因子：
4.5
通讯作者：
Johnson DL
中科院分区：
文献类型：
--
作者：
Palian BM;Rohira AD;Johnson SA;He L;Zheng N;Dubeau L;Stiles BL;Johnson DL
Maf1 最初被鉴定为 RNA pol III 转录基因的转录抑制因子，但对其其他潜在靶基因或其生物学功能知之甚少。在这里，我们证明 Maf1 是 PTEN 的关键下游靶标，驱动其肿瘤抑制和代谢功能。在小鼠模型和人类癌症中，Maf1 表达随着 PTEN 的缺失而减少。与其作为肿瘤抑制因子的作用一致，Maf1 减少了小鼠中锚定非依赖性生长和肿瘤形成。 PTEN 介导的 Maf1 表达变化是由 PTEN 作用于 PI3K/AKT/FoxO1 信号传导介导的，揭示了调节 RNA pol III 依赖性基因的新途径。这一调节事件具有生物学相关性，因为饮食诱导的 PI3K 激活会降低小鼠肝脏中 Maf1 的表达。我们进一步将脂肪生成酶鉴定为一类新的 Maf1 调节基因，其中 FASN 启动子上的 Maf1 占据反对 SREBP1c 介导的转录激活。与这些发现一致的是，Maf1 抑制细胞内脂质积累，并且增加小鼠肝脏中 Maf1 的表达消除了饮食介导的脂肪生成酶和甘油三酯的诱导。总之，这些结果确立了 Maf1 作为 PTEN/PI3K 信号下游效应子的新生物学作用，并揭示 Maf1 是该通路共同调节脂质代谢和肿瘤发生的关键元件。肥胖是人类癌症的一个重要危险因素，但其生物学基础尚不清楚。除了异常生长之外，脂质合成异常也是癌细胞的一个标志。我们的结果确定了 Maf1 在抑制脂质生物发生和肿瘤形成方面的新作用。 Maf1 通过抑制合成脂质和调节生物合成能力的基因来引发这些生物反应。 Maf1 的量通过涉及 PTEN/PI3K/Akt/FoxO1 的关键细胞途径进行调节，该途径在许多人类癌症中不受调节。我们的结果支持这样的观点：癌细胞中这条通路的失调会导致细胞 Maf1 减少，从而导致生长和脂质合成异常。因此，Maf1代表了脂质代谢和致癌转化之间的新联系，为肥胖和癌症之间的密切关联提供了新的分子基础。
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. 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.
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影响因子：
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