TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup

Abstract

Purpose Current clinical parameters do not stratify indolent from aggressive prostate cancer (PCa). Aggressive PCa, defined by the progression from localized disease to metastasis, is responsible for the majority of PCa-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of PCa patients, however they have yet to provide targeted therapy approaches that could inhibit a patient’s progression to metastatic disease. Experimental Design We have interrogated a total of seven primary PCa cohorts (N = 1,900), two metastatic castration resistant PCa datasets (N = 293) and one prospective cohort (N = 1,385) to assess the impact of TOP2A and EZH2 expression on PCa cellular program and patient outcomes. We also performed immunohistochemical staining for TOP2A and EZH2 in a cohort of primary PCa patients (N = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel PCa-derived murine cell lines. Results We demonstrate by genome-wide analysis of independent primary and metastatic PCa datasets that concurrent TOP2A and EZH2 mRNA and protein up-regulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in PCa cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions Overall, our data supports further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neo-adjuvant targeted therapy approaches.

Up-regulation of exosomal miR-125a in pneumoconiosis inhibits lung cancer development by suppressing expressions of EZH2 and hnRNPK

“…Some studies have indicated that an elevated expression level of EZH2 might be potentially used as a biomarker for the diagnosis of prostate cancer. 38,39 Typically, the expression of EZH2 has been detected to be up-regulated in non-small-cell lung cancer, 40,41 which was consistent with the ndings in this study.…”

Expression profiles analysis identifies the values of carcinogenesis and the prognostic prediction of three genes in adrenocortical carcinoma

“…Its enzyme is a marker of cell proliferation in normal and tumor tissue (28). TOP2A was confirmed to be involved in epigenetic regulation through enhancer of zeste homolog 2, and aberrant expression of TOP2A was correlated with malignant characteristics of prostate cancer (29,30). In the present study, TOP2A was upregulated in ACC compared with ACA according to microarray data, which was confirmed by RT-qPCR.…”

Identifying Tumorigenesis and Prognosis-Related Genes of Lung Adenocarcinoma: Based on Weighted Gene Coexpression Network Analysis

“…On the contrary, the predictive roles of MAD2L1 and ZWINT for LUADs have been reported [43,44]. Moreover, TOP2A (DNA topoisomerase II alpha) encodes a DNA topoisomerase which is a well-studied cancer-associated protein [45]. Several anticancer agents targeting DNA topoisomerase have been applied in clinical practice [46].…”