Glycolysis reprogramming predicts poor prognosis and drives therapy resistance via CLN6 in lethal prostate cancer

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 confirm 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]. In contrast to normal cells, which primarily rely on oxidative phosphorylation (OXPHOS) for energy production, tumor cells exhibit a pronounced preference for glycolysis. Despite generating less ATP per glucose molecule, glycolysis offers a faster rate of energy production, enabling tumor cells to meet the heightened metabolic demands of proliferation and survival [7,8]. For instance, in pancreatic cancer, activation of the GFRA2-RET signaling axis by neurturin enhances glycolysis through phosphorylation of hexokinase 2, thereby driving tumor progression [9]. Similarly, in colorectal cancer, ATF4 promotes tumor growth by upregulating glycolytic activity [10]. In lethal prostate cancer, emerging evidence highlights the role of glycolysis in mediating treatment resistance [11]. However, the intricate regulatory networks governing glycolysis necessitate further investigation to fully elucidate its mechanistic contributions to cancer progression and resistance.