Poly (ADP-ribose) polymerase-1 (PARP-1) is a multifunctional, chromatin-regulating protein. PARP inhibitors are currently undergoing clinical trials as potential targeted therapies for the treatment of breast, uterine, colorectal, and ovarian cancer.
Poly (ADP-ribose) polymerase-1 (PARP-1) is a multifunctional, chromatin-regulating protein. PARP inhibitors are currently undergoing clinical trials as potential targeted therapies for the treatment of breast, uterine, colorectal, and ovarian cancer.1These drugs may make use of the phenomenon of synthetic lethality, whereby cells deficient in one DNA repair pathway are targeted by inhibiting another repair pathway.2
Breast cancer develops and progresses in response to uncontrolled gene expression that allows cells to escape regulated cell growth and normal cell protection programs. Histone-modifying enzymes interact with the complex of histone proteins and genomic DNA, called chromatin, within cell nuclei to affect the regulation of gene expression. If these histone-modifying enzymes are over- or under-expressed, it can deregulate the chromatin-dependent gene regulatory process and lead to tumor development.
PARP-1 has been shown to interact with breast-cancer-related histone-modifying enzymes and regulate gene expression in breast cancer cells, turning some genes on and other genes off. Results of genomic analyses3conducted in MCF-7 human breast cancer cell lines have localized PARP-1 to active gene promoters and demonstrated that PARP-1 modulates the modification state of histones.
Specifically, PARP-1 promotes H3K4 trimethylation [activation] and inhibits H3K27 trimethylation [repression]. Previous studies have demonstrated that PARP1 is a critical regulator of estrogen receptor-α (ERα)-dependent gene transcription in cultured visceral smooth muscle cells by binding to ERα in the nucleus, increasing the DNA binding capacity of ERα, and promoting ERα-dependent gene transcription.4
“In our current study, we have explored the role of PARP-1 in estrogen-dependent gene regulation in ERα-positive breast cancers. We find that PARP-1 knockdown affects estrogen-dependent gene expression and proliferation of MCF-7 cells,” said Shrikanth S. Gadad, PhD, of the UT Southwestern Medical Center in Dallas, on March 7, 2015, at the 97thAnnual Meeting of the Endocrine Society. This abstract was the winner of an Outstanding Abstract Award.
To address the hypothesis that PARP-1 controls chromatin dynamics and regulates estrogen-regulated transcription, the genomic assay, Global nuclear Run-On and Sequencing (GRO-Seq), was used to measure both annotated and unannotated transcription by RNA polymerases I, II, and III in estrogen-treated MCF-7 cells with or without PARP-1 knockdown. Systematic analysis of GRO-Seq data generated a comprehensive transcriptional profile of protein-coding and non-coding genes co-regulated by estrogen and PARP-1 in the MCF-7 cells. Subsequent ChIP-Seq analyses revealed that PARP-1 directly regulates the ligand-dependent binding of ERα to a subset of its genomic binding sites.
“Finally, we found that the expression levels of the PARP-1- and estrogen-regulated gene set correlate with the expression of PARP-1 in different grades of ER-positive breast cancer tumors. Taken together, the current study suggests that PARP-1 regulates critical molecular pathways that underlie proliferation of breast cancer cells,” Gadad concluded.