An androgen receptor-based signature to predict prognosis and identification of ORC1 as a therapeutical target for prostate adenocarcinoma

Linjin Li; Dake Chen; Xiang Chen; Jianlong Zhu; Wenshuo Bao; Chengpeng Li; Feilong Miao; Rui Feng

doi:10.7717/peerj.16850

An androgen receptor-based signature to predict prognosis and identification of ORC1 as a therapeutical target for prostate adenocarcinoma

PeerJ. 2024 Mar 29:12:e16850. doi: 10.7717/peerj.16850. eCollection 2024.

Authors

Linjin Li¹, Dake Chen¹, Xiang Chen¹, Jianlong Zhu¹, Wenshuo Bao¹, Chengpeng Li¹, Feilong Miao¹, Rui Feng²

Affiliations

¹ Department of Urology, The Third Clinical Institute Affiliated to Wenzhou Medical University, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, WenZhou, Zhejiang, China.
² Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang, Jiangsu, China.

Abstract

Background: Aberrant activation of androgen receptor (AR) signaling plays a crucial role in the progression of prostate adenocarcinoma (PRAD) and contributes significantly to the development of enzalutamide resistance. In this study, we aimed to identify a novel AR-driven signature that can predict prognosis and endows potentially reveal novel therapeutic targets for PRAD.

Methods: The Seurat package was used to preprocess the single-cell RNA sequencing (scRNA-seq). Differentially expressed genes were visualized using limma and pheamap packages. LASSO and multi-variate Cox regression models were established using glmnet package. The package "Consensus Cluster Plus" was utilized to perform the consensus clustering analysis. The biological roles of origin recognition complex subunit 1 (ORC1) in PRAD were determined by gain- and loss-of-function studies in vitro and in vivo.

Result: We characterized the scRNA-seq data from GSE99795 and identified 10 AR-associated genes (ARGs). The ARGs model was trained and validated in internal and external cohorts. The ARGs were identified as an independent hazard factor in PRAD and correlated with clinical risk characteristics. In addition, the ARGs were found to be correlated with somatic tumor mutation burden (TMB) levels. Two groups that have distinct prognostic and molecular features were identified through consensus clustering analysis. ORC1 was identified as a critical target among these ARGs, and it ORC1 promoted proliferation and stem-like properties of PRAD cells. Chromatin immunoprecipitation (ChIP)-qPCR assay confirmed that AR could directly bind the promoter of ORC1. Activated AR/ORC1 axis contributed to enzalutamide resistance, and targeting ORC1 rendered PRAD cells more susceptible to enzalutamide.

Conclusions: This study defines an AR-driven signature that AR activates ORC1 expressions to promote PRAD progression and enzalutamide resistance, which may provide novel targets for PRAD treatment.

Keywords: AR-driven signature; Enzalutamide; ORC1; Prognosis; scRNA-seq.

MeSH terms

Adenocarcinoma* / drug therapy
Benzamides*
Drug Resistance, Neoplasm / genetics
Humans
Male
Nitriles*
Origin Recognition Complex
Phenylthiohydantoin*
Prostate / metabolism
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Receptors, Androgen / genetics

Substances

Receptors, Androgen
enzalutamide
ORC1 protein, human
Origin Recognition Complex
Benzamides
Nitriles
Phenylthiohydantoin

Grants and funding

The project was supported by the Basic Research Programs of Science and Technology Department of Wenzhou (Y20210171) and the Wenzhou associated of the Integration of Traditional and Western Medicine, clinical research fund (2021004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.