Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation

Abstract

Emerging evidence associates translation factors and regulators to tumorigenesis. However, our understanding of translational changes in cancer resistance is still limited. Here, we generated an enzalutamide-resistant prostate cancer (PCa) model, which recapitulated key features of clinical enzalutamide-resistant PCa. Using this model and poly(ribo)some profiling, we investigated global translation changes that occur during acquisition of PCa resistance. We found that enzalutamide-resistant cells exhibit an overall decrease in mRNA translation with a specific deregulation in the abundance of proteins involved in mitochondrial processes and in translational regulation. However, several mRNAs escape this translational downregulation and are nonetheless bound to heavy polysomes in enzalutamide-resistant cells suggesting active translation. Moreover, expressing these corresponding genes in enzalutamide-sensitive cells promotes resistance to enzalutamide treatment. We also found increased association of long non-coding RNAs (lncRNAs) with heavy polysomes in enzalutamide-resistant cells, suggesting that some lncRNAs are actively translated during enzalutamide resistance. Consistent with these findings, expressing the predicted coding sequences of known lncRNAs JPX, CRNDE and LINC00467 in enzalutamide-sensitive cells drove resistance to enzalutamide. Taken together, this suggests that aberrant translation of specific mRNAs and lncRNAs is a strong indicator of PCa enzalutamide resistance, which points towards novel therapeutic avenues that may target enzalutamide-resistant PCa.

scTIGER: A Deep-Learning Method for Inferring Gene Regulatory Networks from Case versus Control scRNA-seq Datasets

“…These findings align with previous studies indicating that alterations in calcium regulation and vesicle trafficking can promote the growth and metastasis of PCa [42][43][44]. Second, scTIGER detected AR-regulated genes associated with changes in the initiation steps of translation, resulting in an overall decrease in mRNA translation in PCa [45,46]. Specifically, scTIGER identified AR downregulating NSUN6 expression in PCa, and it has been shown that mRNAs associated with NSUN6 exhibit higher rates of translation, thus causing a decrease in overall translation [47].…”

Combined transcriptomics and proteomics unveil the impact of vitamin C in modulating specific protein abundance in the mouse liver

“…Isolation of polysomal associated RNAs and polysomal profiles analysis were performed like previously described [ 38 ]. Briefly, livers from male Gulo −/− mice treated with 0% or 0.4% ascorbate were homogenized on ice by 10 strokes in an ice-cold Dounce homogenizer with 2 ml of lysis buffer (20 mM Tris, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 40 U/mL Rnasin, 50 µg/mL cycloheximide, cOmplete™ EDTA-free Protease Inhibitor Cocktail (Roche, Indianapolis, IN, USA) and 1 mM dithiothreitol), and Nonidet P-40 substitute and sodium deoxycholate was added to a final concentration of 1% for lysis.…”

“…area corresponding to peaks of the 40 S, 60 S and 80 S ribosomal sub-units) and for polysomal fractions (i.e. area from the first polysomal peak to the twelfth polysomal peak, as reported [ 38 ]). The values for the lower limit of the Y axis were defined by the lowest points on each graph.…”