PTEN is implicated in a wide variety of pathophysiological conditions and traditionally studied in the context of the PIK3-AKT–mTOR axis. Recent studies from our group and others have reported a novel role of PTEN in the regulation of transcription at the genome-wide scale. This emerging role of PTEN on global transcriptional regulation is providing a better understanding of various diseases, including cancer. Since cancer progression is an energy-demanding process and PTEN is known to regulate metabolic processes, we sought to understand the role of PTEN in transcriptional regulation under metabolic stress, a condition often developing in the tumor microenvironment. In the present study, we demonstrate that PTEN modulates genome-wide RNA Polymerase II (Pol II) occupancy in cells undergoing glucose deprivation. The glucose-deprived PTEN null cells were found to continue global gene transcription, which may activate a survival mode. However, cells with constitutive PTEN expression slow transcription, an evolutionary mechanism that may save cellular energy and activate programmed cell death pathways, in the absence of glucose. Interestingly, alternative exon usage by PTEN null cells is increased under metabolic stress compared to PTEN expressing cells. Overall, our study demonstrates distinct mechanisms involved in PTEN-dependent genome-wide transcriptional control under metabolic stress. Our findings provide a new insight in understanding tumor pathology and how PTEN loss of function, whether by genetic or non-genetic mechanisms, can contribute to a favorable transcriptional program employed by tumor cells to escape apoptosis, hence developing more aggressive and metastatic phenotypes.

中文翻译：

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代谢应激以 PTEN 依赖性方式调节全基因组转录。

PTEN 涉及多种病理生理条件，传统上在 PIK3-AKT-mTOR 轴的背景下进行研究。我们小组和其他人最近的研究报告了 PTEN 在全基因组尺度转录调控中的新作用。PTEN 在全球转录调控中的这种新兴作用提供了对包括癌症在内的各种疾病的更好理解。由于癌症进展是一个需要能量的过程，并且已知 PTEN 调节代谢过程，我们试图了解 PTEN 在代谢应激下转录调节中的作用，这种情况经常发生在肿瘤微环境中。在本研究中，我们证明 PTEN 调节经历葡萄糖剥夺的细胞中的全基因组 RNA 聚合酶 II (Pol II) 占据。发现葡萄糖剥夺的 PTEN 无效细胞继续全局基因转录，这可能会激活生存模式。然而，在没有葡萄糖的情况下，具有组成型 PTEN 表达的细胞会减慢转录，这是一种可以节省细胞能量并激活程序性细胞死亡途径的进化机制。有趣的是，与表达 PTEN 的细胞相比，在代谢应激下 PTEN 无效细胞的替代外显子使用增加。总体而言，我们的研究证明了代谢应激下 PTEN 依赖性全基因组转录控制所涉及的不同机制。我们的发现为理解肿瘤病理学以及 PTEN 的功能丧失（无论是通过遗传还是非遗传机制）如何促进肿瘤细胞采用有利的转录程序以逃避细胞凋亡提供了新的见解，