Metabolic stress regulates genome-wide transcription in a PTEN-dependent manner

Abstract

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.

Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts

“…The response of cancer cells to glucose starvation has been extensively investigated by several previous studies, which highlighted multiple intrinsic mechanisms, in line with results of our study [ 53 – 57 ]. It is also important to underline that although here we focused on clones derived from established cancer cell lines, our group previously demonstrated that GDR/GDS populations exist also in OC patient-derived samples [ 58 ], thus underscoring the translational relevance of our findings.…”