PARP-1 Has Role in Estrogen-Related Transcription

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 97^thAnnual 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.

References

1. Rouleau M, Patel A, Hendzel MJ et al. PARP inhibition: PARP1 and beyond.Nat Rev Cancer. 2010;10:293-301.
2. Rowe BP, Glazer PM. Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms.Breast Cancer Res. 2010;12:203.
3. Gadad SS, Chae M, Hussey KM, et al. The role of PARP-1 in estrogen-regulated transcription. Presented at the 2015 Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA. Poster Board SAT-270.
4. Zhang F, Wang Y, Wang L, et al. Poly(ADP-ribose) polymerase 1 is a key regulator of estrogen receptor alpha-dependent gene transcription.J Biol Chem. 2013;288:11348-11357.