Identification and verification of an ALYREF-involved 5-methylcytosine based signature for stratification of prostate cancer patients and prediction of clinical outcome and response to therapies

Xiao Tan; Zhouda Cai; Guo Chen; Chao Cai; Jiahong Chen; Yingke Liang; Yangjia Zhuo; Jianming Liu; Liangliang Huang; Bin Ouyang; Yanni Wei; Zhenyu Jia; Junhong Deng; Weide Zhong; Jianming Lu

doi:10.1007/s12672-023-00671-w

Identification and verification of an ALYREF-involved 5-methylcytosine based signature for stratification of prostate cancer patients and prediction of clinical outcome and response to therapies

Discov Oncol. 2023 May 8;14(1):62. doi: 10.1007/s12672-023-00671-w.

Authors

Xiao Tan^#^{1

2}, Zhouda Cai^#^{1

3}, Guo Chen^#⁴, Chao Cai⁵, Jiahong Chen⁶, Yingke Liang³, Yangjia Zhuo³, Jianming Liu¹, Liangliang Huang¹, Bin Ouyang¹, Yanni Wei¹, Zhenyu Jia⁷, Junhong Deng⁸, Weide Zhong^{9

10

11}, Jianming Lu^{12

13}

Affiliations

¹ Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China.
² Department of Urology, School of Clinical Medicine, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, Sichuan, China.
³ Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China.
⁴ Department of Urology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
⁵ Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, 510120, Guangdong, China.
⁶ Department of Urology, Huizhou Municipal Central Hospital, Huizhou, 516001, Guangdong, China.
⁷ Department of Botany and Plant Sciences, University of California, Riverside, CA, 92521, USA.
⁸ Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China. eydengjh@scut.edu.cn.
⁹ Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China. eyweidezhong@scut.edu.cn.
¹⁰ Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, 510120, Guangdong, China. eyweidezhong@scut.edu.cn.
¹¹ Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China. eyweidezhong@scut.edu.cn.
¹² Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China. louiscfc8@gmail.com.
¹³ Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China. louiscfc8@gmail.com.

^# Contributed equally.

Abstract

Objectives: Due to the heterogeneity of PCa, the clinical indicators used for PCa can't satisfy risk prognostication and personalized treatment. It is imperative to develop novel biomarkers for prognosis prediction and therapy response in PCa. Accumulating evidence shows that non-mutational epigenetic reprogramming, independent from genomic instability and mutation, serves as a newly added hallmark in cancer progression.

Methods: In this study, we integrated multi-center cohorts (N > 1300) to develop a RNA 5-methylcytosine regulator-based signature, the m5C score. We performed unsupervised clustering and LASSO regression to identify novel m5C-related subtypes and calculate the m5C score. Then we assessed the role of m5C cluster and m5C score in several clinical aspects such as prognosis in various molecular subtypes, responses to chemotherapy, androgen receptor signaling inhibitor (ARSI) therapy and immunotherapy in PCa. Finally, we validated the cancer-promoting performance of ALYREF through clinical data analysis and experiments in vivo and in vitro.

Results: The investigation revealed that the m5C score could accurately predict the biochemical recurrence (BCR) in different subtypes (the PAM50 subtypes and immunophenotypes) and the responses to chemotherapy, ARSI therapy, and immunotherapy (PD1/PD-L1). A high m5C score indicated a poor BCR prognosis in every subtype of PCa, unfavorable responses in ARSI therapy and immunotherapy (PD1/PD-L1). Moreover, the m5C reader gene termed ALYREF, yielding the highest weighed coefficient, promoted PCa progression through in silico analysis and experimental validations (in vivo and in vitro).

Conclusions: The m5C signature can function in many aspects of PCa, such as the development and prognosis of the disease, and multiple therapy responses. Further, the m5C reader, ALYREF, was identified as a prognostic biomarker and a potential therapeutic target for PCa. The m5C signature could act as a brand-new tool for predicting the prognosis of patients in different molecular subtypes and patients' therapy responses and promoting customized treatments.

Keywords: Androgen receptor signaling inhibitor; Biochemical recurrence; Epigenetics; Immunotherapy; Prostate cancer; RNA 5-methylcytosine.