Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Developmental Therapeutics Program, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44116, USA.
Hum Mol Genet. 2020 Sep 29;29(16):2736-2745. doi: 10.1093/hmg/ddaa168.
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. Because 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 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 in contrast 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.
PTEN 涉及多种病理生理状况，传统上在 PIK3-AKT-mTOR 轴的背景下进行研究。我们小组和其他小组的最近研究报告了 PTEN 在全基因组转录调控中的新作用。PTEN 对全球转录调控的这种新作用为理解各种疾病（包括癌症）提供了更好的认识。由于癌症的进展是一个需要能量的过程，并且已知 PTEN 调节代谢过程，因此我们试图了解代谢应激下 PTEN 在转录调控中的作用，这是肿瘤微环境中经常发生的情况。在本研究中，我们证明了 PTEN 在经历葡萄糖剥夺的细胞中调节全基因组 RNA 聚合酶 II 占据。发现缺乏葡萄糖的 PTEN 缺失细胞继续进行全局基因转录，这可能激活了一种生存模式。然而，在没有葡萄糖的情况下，具有组成型 PTEN 表达的细胞会减缓转录，这是一种可能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，代谢应激下 PTEN 缺失细胞的选择性外显子使用增加。总体而言，我们的研究表明，在代谢应激下，PTEN 依赖的全基因组转录控制涉及不同的机制。我们的发现为理解肿瘤病理学以及 PTEN 功能丧失（无论是遗传还是非遗传机制）如何有助于肿瘤细胞逃避凋亡的有利转录程序提供了新的见解，从而发展出更具侵袭性和转移性的表型。
