Key Takeaways & Executive Findings
- •• Elevated glycolysis activity is associated with poor survival in lethal prostate cancer. • A six-gene glycolysis-based prognostic score (GLY score) effectively stratifies patient risk. • Enzalutamide-resistant prostate cancer cells exhibit heightened glycolysis, and 2-DG inhibition restores drug sensitivity. • CLN6 knockdown reduces glycolytic activity and cell proliferation, highlighting its potential as a therapeutic target.
Abstract
Lethal prostate cancer is marked by tumor heterogeneity and resistance to androgen receptor signaling inhibitors (ARSIs). In this study, we identify glycolysis as a driver of disease progression and therapy resistance. Using single-sample gene set enrichment analysis (ssGSEA) on the SU2C cohort, we demonstrate that elevated glycolysis activity is associated with poor progression-free and overall survival. The glycolysis-based prognostic score (GLY score) is derived from the HALLMARK_GLYCOLYSIS gene set, which includes CLN6, SDHC, B4GALT2, RPE, NANP, and KIF20A, via LASSO-Cox regression. The GLY score effectively stratifies risk in the SU2C and WDCT cohorts, with higher scores predicting worse outcomes and increased SYNE1 mutation frequency. Pan-cancer analysis across TCGA datasets confirms its prognostic value. In vitro, enzalutamide-resistant prostate cancer cell lines exhibit heightened glycolysis, and 2-DG inhibition reverses this effect, restoring drug sensitivity. CLN6 knockdown reduces glycolytic activity and cell proliferation. The GLY score offers robust prognostic value, and CLN6 represents a promising therapeutic target for precision medicine in lethal prostate cancer.
1. Introduction
Prostate cancer ranks as the second most prevalent malignancy among men globally, contributing to over 10% of cancer-related mortality and standing as the fifth leading cause of cancer deaths worldwide [1]. In its localized stage, prostate cancer typically exhibits indolent growth, with patients often achieving favorable outcomes through surgical resection or radiotherapy. Over the recent decades, advancements in diagnostic techniques and therapeutic strategies have significantly enhanced the management of lethal prostate cancer, particularly through androgen deprivation therapy (ADT) and AR signaling inhibitors (ARSIs), including abiraterone, enzalutamide, apalutamide, and darolutamide, which have conferred substantial survival benefits [2,3].
Nevertheless, to further optimize patient prognosis, a deeper understanding of the complex interplay between molecular drivers and dysregulatory mechanisms that propel lethal prostate cancer progression is essential. The marked heterogeneity of lethal prostate cancer, coupled with the diverse clinical presentations observed across patients, poses challenges to such investigations. However, by focusing on prevalent genetic mutations and regulatory pathways, research findings are more likely to translate effectively into clinical practice, offering broader applicability and impact [4]. Metabolic reprogramming is a hallmark of tumor heterogeneity and therapy resistance, with glycolysis playing a pivotal role [5,6].
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CAI Zhouda, LU Jianming, MO Shanshan, LIU Jipu, ZHONG Chuanfan, WU Yongding, ZOU Fen, YE Jianheng, HAN Zhaodong, LIANG Yuxiang, ZHANG Le, LIU Fengping, ZHONG Weide (2026). Glycolysis Reprogramming Predicts Poor Prognosis and Drives Therapy Resistance via CLN6 in Lethal Prostate Cancer. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025257
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Frequently Asked Questions
What is the GLY score in prostate cancer?
The GLY score is a prognostic signature derived from six glycolysis-related genes (CLN6, SDHC, B4GALT2, RPE, NANP, KIF20A) using LASSO-Cox regression. It stratifies patients into high- and low-risk groups, with higher scores predicting worse outcomes and increased mutation frequency.
How does glycolysis contribute to therapy resistance in prostate cancer?
Glycolysis is upregulated in enzalutamide-resistant prostate cancer cells, and inhibiting glycolysis with 2-DG restores drug sensitivity, indicating that metabolic reprogramming drives resistance to AR signaling inhibitors.
What is the role of CLN6 in prostate cancer?
CLN6 is identified as a novel hub gene in the glycolytic pathway of lethal prostate cancer. Knockdown of CLN6 reduces glycolytic activity and cell proliferation, suggesting it as a potential therapeutic target.
How was the GLY score validated?
The GLY score was validated in the SU2C and WDCT cohorts, and its prognostic value was confirmed across multiple TCGA pan-cancer datasets.
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