MiR-378a inhibits glucose metabolism by suppressing GLUT1 in prostate cancer

A Cannistraci,N W Clarke,P Hascoet,P Mundra,V Pavet,A Ali,R Marais

doi:10.1038/s41388-022-02178-0

A Cannistraci, N W Clarke + Show 5 more

Open Access

https://doi.org/10.1038/s41388-022-02178-0

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Abstract

Prostate cancer (PCa) is the fifth leading cause of cancer related deaths worldwide, in part due to a lack of molecular stratification tools that can distinguish primary tumours that will remain indolent from those that will metastasise. Amongst potential molecular biomarkers, microRNAs (miRs) have attracted particular interest because of their high stability in body fluids and fixed tissues. These small non-coding RNAs modulate several physiological and pathological processes, including cancer progression. Herein we explore the prognostic potential and the functional role of miRs in localised PCa and their relation to nodal metastasis. We define a 7-miR signature that is associated with poor survival independently of age, Gleason score, pathological T state, N stage and surgical margin status and that is also prognostic for disease-free survival in patients with intermediate-risk localised disease. Within our 7-miR signature, we show that miR-378a-3p (hereafter miR-378a) levels are low in primary tumours compared to benign prostate tissue, and also lower in Gleason score 8–9 compared to Gleason 6–7 PCa. We demonstrate that miR-378a impairs glucose metabolism and reduces proliferation in PCa cells through independent mechanisms, and we identify glucose transporter 1 (GLUT1) messenger RNA as a direct target of miR-378a. We show that GLUT1 inhibition hampers glycolysis, leading to cell death. Our data provides a rational for a new PCa stratification strategy based on miR expression, and it reveals that miR-378a and GLUT1 are potential therapeutic targets in highly aggressive glycolytic PCa.

Highlights

Prostate cancer (PCa) is the second most common cancer in men [1] and its detection and reported incidence have increased over the past two decades, in part due to widespread PSA testing, in the developed world
We define a 7-miR signature that is prognostic in patients where clinical decisions must balance the uncertainty of progression against treatments that could cause severe morbidity without benefit, and we show a key role of miR-378a in regulating PCa metabolism, allowing us to identify glucose transporter 1 (GLUT1) as a therapeutic target in early stage PCa with glycolytic features
We showed that miR-378a levels were sion, we examined whether the presence of specific miRs in significantly lower in 22Rv1, LNCaP, PC3 and DU145 cancer cells primary tumours could identify which patients would develop metastasis

Summary

Introduction

Prostate cancer (PCa) is the second most common cancer in men [1] and its detection and reported incidence have increased over the past two decades, in part due to widespread PSA testing, in the developed world. Current efforts to develop biomarkers for risk stratification in PCa include assessment of DNA and RNA indices [2, 3], but the RNA indices largely exclude microRNAs (miRs), highly conserved small (21–23nt) noncoding RNA molecules that regulate many cellular processes in response to endogenous and exogenous stimuli [4]. MiRs function to fine-tune cell behaviour by modulating rapid post-transcriptional changes in cellular proteomes by degrading target mRNAs, or inhibiting their translation; notably, miR expression patterns are altered in many diseases including PCa [5, 6]. We analyse miR expression in primary PCa and identify seven fully processed miRs associated with nodal metastasis. We demonstrate that these miRs can segregate patients with localised

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