c-MYC Suppresses BIN1 to Release Poly(ADP-Ribose) Polymerase 1: A Mechanism by Which Cancer Cells Acquire Cisplatin Resistance

Abstract

Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of cancer cells to cisplatin depended on BIN1 abundance, regardless of the p53 gene status. BIN1 bound to the automodification domain of and suppressed the catalytic activity of poly(ADP-ribose) polymerase 1 (PARP1, EC 2.4.2.30), an enzyme essential for DNA repair, thereby reducing the stability of the genome. The inhibition of PARP1 activity was sufficient for BIN1 to suppress c-MYC-mediated transactivation, the G(2)-M transition, and cisplatin resistance. Conversely, overexpressed c-MYC repressed BIN1 expression by blocking its activation by the MYC-interacting zinc finger transcription factor 1 (MIZ1) and thereby released PARP1 activity. Thus, a c-MYC-mediated positive feedback loop may contribute to cancer cell resistance to cisplatin.

Regulation of E2F1-induced apoptosis by poly(ADP-ribosyl)ation

“…This is probably attributable to the lack of endogenous c-Myc after serum withdrawal in untransformed cells, as PARP1 expression and activity are activated by c-MYC. 27,28 These results suggest that PARP1 post-translationally modifies E2F1 by poly(ADP-ribosyl)ation, which subsequently stabilizes the E2F1-DNA promoter interaction, and negatively regulates E2F1-dependent gene transcription. +/+ and Parp1 -/-fibroblasts with E2A-Luc, an adenoviral E2A-promoter-driven luciferase reporter vector.…”

“…We have previously reported that the BIN1 BAR-C domain (the carboxyl-terminal half of the BAR domain) is sufficient to interact with PARP1. 27 Because the same BIN1 BAR-C domain was required for BIN1-E2F1 binding (see above; Figure 4b), we wondered whether PARP1 might disrupt the BIN1-E2F1 interaction. However, a co-IP/western blot analysis demonstrated that the BIN1-E2F1 association in vivo was even stabilized in the presence of PARP1 (Figure 5a).…”

“…Because PARP1 per se has no structural features characteristic of a transcriptional corepressor, 20,21 we hypothesized that PARP1 recruits a corepressor to the vicinity of E2F1. Among a number of PARP1-interacting proteins in the nucleus, the bridging integrator 1 (BIN1) protein, 27 which was originally identified as a MYC-interacting proapoptotic tumor suppressor, 29 acts as a broad transcriptional corepressor. 30 Co-immunoprecipitation (co-IP) experiments followed by western blot analysis revealed that BIN1 -/-mouse-embryo fibroblasts (MEFs) constitutively expressing the ER-E2F1 fusion protein (MEF E2f1 − / − ER-E2F1), which were cultured for 48 h in growth medium (supplemented with 10% Charcoal/Dextran (CD)-treated fetal bovine serum (FBS)) in the presence (+) or absence (-) of olaparib (10 μM) and 4-OHT (20 nM).…”

“…It is well known that BIN1 suppresses oncogenic transformation 29,30 by stimulating apoptotic cell death 14,27,35,36 and/or arresting the cell cycle. 15,27,31 To determine whether the induction of endogenous BIN1 mediated by PARP1 attenuation is biologically germane, we performed several cell-based assays. First, three different pharmacological PARP inhibitors, niraparib, olaparib, and veliparib, demonstrate different cytotoxic and cytostatic effects in cancer cells, 34 so we hypothesized that a more powerful PARP inhibitor should induce more BIN1 expression.…”

To die, or not to die: E2F1 never decides by itself during serum starvation

“…7 Using a proteomic approach, we pulled down poly(ADP-ribose) polymerase-1 (PARP1), a nuclear enzyme that controls genomic stability, chromatin remodeling, gene transcription, and apoptosis, as a new BIN1-interacting protein. 9 Because E2F1 also physically interacts with PARP1, 10 we wondered whether PARP1 might have any positive or negative impact on the E2F1-BIN1 interaction in vivo. We found that PARP1 stabilizes the E2F1-BIN1 association on an E2F-sensitive gene promoter, and that PARP1 posttranslationally modifies E2F1 by poly (ADP-ribosyl)ation.…”