Multiplex Assay for Activated p300/CBP in Circulating Prostate Tumor Cells | Oncotarget
Channel: Oncotarget
Date: 2023-07-21

Oncotarget published this research paper on July 20, 2023 in Volume 14, entitled, “Development of a multiplex assay to assess activated p300/CBP in circulating prostate tumor cells” by researchers from the Department of Urology, School of Medicine and Public Health, University of Wisconsin, Madison, WI; Department of Hematology/Oncology, University of Wisconsin, Madison, WI; Biomolecular Chemistry, University of Wisconsin, Madison, WI; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI. @uwmadison 
#cancer  #prostatecancer  #tumors  #cells  #cancerresearch  #research  #researchpaper  #openaccess  #openscience   #peerreview   #journal   #publication  #meded  #publishing  

DOI - https://doi.org/10.18632/oncotarget.28477

Correspondence to - David F. Jarrard - jarrard@urology.wisc.edu

Abstract

Reduced SIRT2 deacetylation and increased p300 acetylation activity leads to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in castration-resistant prostate cancer (CRPC). We examined whether circulating tumor cells (CTCs) identify patients with altered p300/CBP acetylation. CTCs were isolated from 13 advanced PC patients using Exclusion-based Sample Preparation (ESP) technology. Bound cells underwent immunofluorescent staining for histone modifying enzymes (HMEs) of interest and image capture with NIS-Elements software. Using the cBioPortal PCF/SU2C dataset, the response of CRPC to androgen receptor signaling inhibitors (ARSI) was analyzed in 50 subjects. Staining optimization and specificity revealed clear expression of acetyl-p300, acetyl-H3K18, and SIRT2 on CTCs (CK positive, CD45 negative cells). Exposure to A-485, a selective p300/CBP catalytic inhibitor, reduced p300 and H3K18 acetylation. In CRPC patients, a-p300 strongly correlated with its target acetylated H3k18 (Pearson’s R = 0.61), and SIRT2 expression showed robust negative correlation with a-H3k18 (R = −0.60). A subgroup of CRPC patients (6/11; 55%) demonstrated consistent upregulation of acetylation based on these markers. To examine the clinical impact of upregulation of the CBP/p300 axis, CRPC patients with reduced deacetylase SIRT2 expression demonstrate shorter response times to ARSI therapy (5.9 vs. 12 mo; p = 0.03). A subset of CRPC patients demonstrate increased p300/CBP activity based on a novel CTC biomarker assay. With further development, this biomarker suite may be used to identify candidates for CBP/p300 acetylation inhibitors in clinical development.

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Keywords - prostate cancer, circulating tumor cells, p300/CBP

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