Intron retention is a hallmark and spliceosome represents a therapeutic vulnerability in aggressive prostate cancer

Abstract

The role of dysregulation of mRNA alternative splicing (AS) in the development and progression of solid tumors remains to be defined. Here we describe the first comprehensive AS landscape in the spectrum of human prostate cancer (PCa) evolution. We find that the severity of splicing dysregulation correlates with disease progression and establish intron retention as a hallmark of PCa stemness and aggressiveness. Systematic interrogation of 274 splicing-regulatory genes (SRGs) uncovers prevalent genomic copy number variations (CNVs), leading to mis-expression of~68% of SRGs during PCa development and progression. Consequently, many SRGs are prognostic. Surprisingly, androgen receptor controls a splicing program distinct from its transcriptional regulation. The spliceosome modulator, E7107, reverses cancer aggressiveness and inhibits castration-resistant PCa (CRPC) in xenograft and autochthonous PCa models. Altogether, our studies establish aberrant AS landscape caused by dysregulated SRGs as a hallmark of PCa aggressiveness and the spliceosome as a therapeutic vulnerability for CRPC.

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

“…The genes with AR binding to this 5kb downstream or upstream of transcription start sites (TSS) were selected as direct AR-bound targets. We next used a transcriptomics dataset generated using RNAi-mediated knockdown of AR 30 and compared gene expression changes in response to AR knockdown. We divided log-fold expression changes into nine equally populated bins, which were also shown along with the patterns of AR enrichment and depletion at the corresponding TSS across the data ( Figure 4A).…”

S-IRFindeR: stable and accurate measurement of intron retention

“…Numerous reports have demonstrated a regulatory role for IR in cell differentiation [9,19,20] and cancer [21][22][23]16]. However contrasting the IR levels of different stages of differentiation or conditions is currently a weak point of all IR detection and estimation algorithms [4].…”

“…One of the assets of RNA-seq technologies for IR studies is to allow transcriptome-wide search for molecular signatures [34,12,16] and biomarkers [11]. To further assess the potential of the SIRratio and the benefits of accurate IR quantitation in large-scale studies, we applied our method to a large time course RNA-seq experiment carried on on H358 cells enduring Epithelial-to-Mesenchymal transition (EMT) [35].…”

“…Though these methods have been recently used to quantify IR events in a wide range of studies [9][10][11][12][13][14][15][16], their capacity to reflect true IR transcripts has not yet undergone thorough validation [3,17]. In fact, several authors including ourselves highlight the high-variability and lack of reproducibility of IR level estimates [3,18].…”

Transcriptomic Analysis Revealed an Emerging Role of Alternative Splicing in Embryonal Tumor with Multilayered Rosettes

“…Cancer cells are capable of dynamically changing gene expression and favoring the expression of aberrant oncogenic splice variants to overcome stresses within the tumor microenvironment [ 38 ]. Abnormal AS is now regarded as a valuable indicator of carcinogenic processes and prognosis, as well as a potential target of treatment in several types of cancer [ 39 , 40 , 41 , 42 , 43 , 44 ].Not only is it a valuable diagnostic marker of ETMRs [ 45 ], LIN28A overexpression can be functionally significant as well. LIN28A was reported as a regulator of self-renewal capacity in cancer stem cells, cellular metabolism, and the cell cycle through binding and repression of let-7 microRNAs [ 12 , 46 , 47 ].…”