Expression of nuclear matrix proteins binding matrix attachment regions in prostate cancer. PARP‐1: New player in tumor progression

Abstract

Prostate cancer (PCa) displays infrequent point mutations, whereas genomic rearrangements are highly prevalent. In eukaryotes, the genome is compartmentalized into chromatin loop domains by the attachment to the nuclear matrix (NM), and it has been demonstrated that several recombination hot spots are situated at the base of loops. Here, we have characterized the binding between NM proteins and matrix attachment regions (MARs) in PCa. Nontumor and 44 PCa tissues were analyzed. More aggressive tumors were characterized by an increase in the complexity of the NM protein patterns that was synchronous with a decrease in the number of proteins binding the MAR sequences. PARP-1 was the protein that showed the most evident changes. The expression of the PARP-1 associated with NM increased and it was dependent on tumor aggressiveness. Immunohistochemical analysis showed that the protein was significantly overexpressed in tumor cells. To explore the role of PARP-1 in PCa progression, PCa cells were treated with the PARP inhibitor, ABT-888. In androgen-independent PC3 cells, PARP inhibition significantly decreased cell viability, migration, invasion, chromatin loop dimensions and histone acetylation. Collectively, our study provides evidence that MAR-binding proteins are involved in the development and progression of PCa. PARP could play a key role in the compartmentalization of chromatin and in the development of the more aggressive phenotype. Thus, PARP can no longer be viewed only as an enzyme involved in DNA repair, but that its role in chromatin modulation could provide the basis for a new therapeutic approach to the treatment of PCa.Although significant advancements have been made in the understanding of the molecular events responsible for the development and progression of prostate cancer (PCa), this tumor remains the most frequently diagnosed among males in economically developed countries.1 The pathogenesis of this cancer is complex; it has an extremely heterogeneous clinical behavior and, different from many other cancers, the events associated with its initiation and progression remain poorly understood.2 Therefore, an improved comprehension of the molecular aspects of PCa progression could help to detect new diagnostic and prognostic markers and define new therapeutic strategies.PCa displays infrequent point mutations, whereas genomic rearrangements are highly prevalent.3 Recently, Baca et al. 4sequenced the whole genomes of 57 PCa cases and identified abundant DNA translocations and deletions. These large-scale chromosomal rearrangements arise through a single and highly interdependent process, rather than through independent multiple steps. The authors coined the term "chromoplexy" to describe this phenomenon of complex genome restructuring. It is known that in eukaryotes, the genome is compartmentalized into chromatin loop domains by the attachment to nuclear matrix (NM). 5 The interactions of chromatin with the NM are a dynamic event that is functionally dependent, 6 and occur via noncoding AT-rich DNA se...

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…In considering the multifaceted role of PARP-1, it is worth mentioning that many reports showed increased levels of PARP-1 or, more generally, pointed to PARP-1 involvement in carcinogenesis, as for instance is the case for primary prostatic cancer [61]. PARP-1 has also been involved in prostate cancer progression, as PARP-1 expression in the nuclear matrix increases with tumor invasiveness [62]. Finally, both enzymatic activity and transcriptional regulatory functions of PARP-1 were reported to be elevated as a function of prostate cancer progression, independently of DNA double strand breaks, but through enhancement of E2F1-mediated induction of DNA repair factors involved in HR [63].…”

Chromatin nanoscale compaction in live cells visualized by acceptor‐to‐donor ratio corrected Förster resonance energy transfer between DNA dyes

“…To this aim, we generated DNA damage on a selected subregion of the nuclei by 405 nm‐laser microirradiation and sensitization with Hoechst 33342, as reported previously . To verify that 405 nm‐laser microirradiation generated local DNA damage in HeLa cell nuclei stained with Hoechst 33342, employed as a sensitizer, we monitored the expression of the DDR marker PARP‐1, a specific protein that rapidly accumulates at genome sites where single‐strand breaks or DSBs have occurred . The expression of PARP‐1 was monitored in cells fixed immediately after microirradiation and in live cells (Figure ).…”

Therapeutic Targeting of Poly(ADP‐Ribose) Polymerase‐1 (PARP1) in Cancer: Current Developments, Therapeutic Strategies, and Future Opportunities

“…Expression levels do not vary significantly in prostate cancers but there are some evident changes observed in context with PARP protein in the nuclear matrix and matrix attachment regions in prostate cancers. PARP1 expression in the nuclear matrix increases with tumor aggressiveness . Transcriptional regulation of some nuclear hormone receptors involves PARP1 and hence PARP could regulate AR target genes.…”

“…PARP1 expression in the nuclear matrix increases with tumor aggressiveness. 65 Transcriptional regulation of some nuclear hormone receptors involves PARP1 and hence PARP could regulate AR target genes. Wang et al have reported a decrease in the AR recruitment to promoters of its target genes in presence of PARPi.…”