PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer

Abstract

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have been evaluated for treating homologous recombination-deficient tumours, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP1 exert several cellular functions unrelated with their role on DNA repair, including function as a co-activator of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumour types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumours. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indications.

PARP1: New Drug Development Opportunities for an Old Target

“…Once released from arrest, cells were treated with the different inhibitors, as shown in Figure 2C. The enzymatic inhibition of PARP1 reduced the transcriptional activity of E2F1 in a manner similar to that of the PARP1 deficiency that we previously reported [9]. Within the experimental groups, we found that PJ34 is possibly the molecule, among the classical inhibitors of PARP1, that reduces this transactivation to a greater extent, while the luciferase activity is reduced by almost 40% compared with the untreated control in cells treated with gossypol.…”

“…As we have already shown [9], Parp1 +/+ cRb -/-HRas V12 astrocytes obtained from P3 neonates present great heterogeneity in their shape and size, together with several morphological alterations, such as the presence of abundant cytoplasmic extensions. Loss of contact inhibition and formation of growth foci in the culture plates, which reflect the existence of a transformed phenotype, was also observed in these cells.…”

“…Indeed, PARP1 can upregulate the transcriptional activity of E2F1 through its function as a co-activator during the re-entry of quiescent cells into S phase [7,8]. Recently, we have shown how PARP1 regulates the E2F1 transcriptional function through their interaction [9]. Here, we show how this transcriptional modulation can be affected by pharmacological treatment with PARP1-interacting molecules.…”

“…In a previous work [9], we have previously described that PARP1 acts as a co-activator of E2F1, and that its deficiency reduces the transcriptional activity of E2F1, thereby reducing tumor growth by decreasing E2F1 hyperactivation. Therefore, here we tested whether this decrease in E2F1 transcriptional activity could be achieved by using several representative examples of the different generations of chemical inhibitors of PARP1.…”

Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

“…Recently PARP-inhibitors have been approved for therapy in PCa patients with DDR pathway mutations and have already been used to treat t-NEPC patients with such aberrations, though only with limited success [ 129 ]. PARP1 is a chromatin associated enzyme modifying various nuclear proteins by poly-ADP-ribosylation, but it also functions as transcriptional coactivator for E2F1 [ 130 ]. In t-NEPC cell models and xenografts, PARP inhibitors have been shown to decrease cell proliferation and tumor growth.…”