Novel chromobox 2 inhibitory peptide decreases tumor progression.

Autor:	Brubaker LW; Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Backos DS; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA., Nguyen VT; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA., Reigan P; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA., Yamamoto TM; Department of Obstetrics & Gynecology, Division of Reproductive Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Woodruff ER; Department of Obstetrics & Gynecology, Division of Reproductive Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Iwanaga R; Department of Obstetrics & Gynecology, Division of Reproductive Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Wempe MF; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA., Kumar V; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA., Persenaire C; Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Watson ZL; Department of Obstetrics & Gynecology, Division of Reproductive Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Bitler BG; Department of Obstetrics & Gynecology, Division of Reproductive Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
Jazyk:	angličtina
Zdroj:	Expert opinion on therapeutic targets [Expert Opin Ther Targets] 2023 Apr-May; Vol. 27 (4-5), pp. 361-371. Date of Electronic Publication: 2023 May 27.
DOI:	10.1080/14728222.2023.2218614
Abstrakt:	Background: The Polycomb Repressor Complex 1 (PRC1) is an epigenetic regulator of differentiation and development, consisting of multiple subunits including RING1, BMI1, and Chromobox. The composition of PRC1 dictates its function and aberrant expression of specific subunits contributes to several diseases including cancer. Specifically, the reader protein Chromobox2 (CBX2) recognizes the repressive modifications including histone H3 lysine 27 tri-methylation (H3K27me3) and H3 lysine 9 dimethylation (H3K9me2). CBX2 is overexpressed in several cancers compared to the non-transformed cell counterparts, it promotes both cancer progression and chemotherapy resistance. Thus, inhibiting the reader function of CBX2 is an attractive and unique anti-cancer approach. Research Design & Methods: Compared with other CBX family members, CBX2 has a unique A/T-hook DNA binding domain that is juxtaposed to the chromodomain (CD). Using a computational approach, we constructed a homology model of CBX2 encompassing the CD and A/T hook domain. We used the model as a basis for peptide design and identified blocking peptides that are predicted to directly bind the CD and A/T-hook regions of CBX2. These peptides were tested in vitro and in vivo models. Conclusion: The CBX2 blocking peptide significantly inhibited both 2D and 3D growth of ovarian cancer cells, downregulated a CBX2 target gene, and blunted tumor growth in vivo.
Databáze:	MEDLINE
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