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Minor intron splicing efficiency increases with the development of lethal prostate cancer

UID: 11313

Author(s): Heller, Manfred, Rubin, Mark A.

Description
Description from PRIDE:

"Minor intron-containing genes (MIGs) are crucial cell cycle regulators and are essential for cell survival. Thus, we explored whether MIGs play a role in cancer progression and cancer therapy resistance. Here we show that MIG-expression segregates sensitive and resistant prostate cancer cells from each other and them from benign tissue. Moreover, the rate of minor intron splicing, a crucial regulatory node for MIG-expression, was more efficient in patients with advanced prostate cancer. We show that the increased minor spliceosome (MiS) activity is downstream of the androgen receptor signaling axis in both therapy sensitive and insensitive prostate cancer types. The increased MiS activity was in line with the elevated expression of U6atac snRNA, a crucial MiS component. We propose the expression of U6atac as a potential point of vulnerability in cancer. MIGs are uniquely susceptible to the MiS, so we used siRNA against ­U6atac, which like protein-coding transcripts, is downregulated. Inhibition of MiS was sufficient to lower the tumor burden significantly in therapy-resistant (prostate) cancer cells and PCa patient-derived organoids. KD cells displayed elevated minor intron retention and alternative splicing across minor introns of MIGs which enriched for MAPK activity, DNA repair and cell cycle regulation. Importantly, these findings were confirmed by MassSpec analysis. Collectively our study nominates the MiS as a driver of highly proliferative, rapidly dividing (prostate) cancer cells that bears strong potential as a therapeutic target for many different cancer types."
Subject of Study
Homo sapiens
Subject(s)
Introns/genetics
Mass spectrometry
Prostatic Neoplasms, Castration-Resistant
Proteomics
OncoTree Cancer Type(s)
Prostate Adenocarcinoma
Access via PRIDE


Accession #: PXD026949

Access via ProteomeXchange.


Accession #: PXD026949

Access Restrictions
Free to All
Access Instructions
Public PXD datasets can be browsed over at ProteomeCentral. An RSS feed is also available. All public datasets available in PRIDE Archive in the repository can be accessed via the website, Web Service (for programmatic access), and the PRIDE Inspector stand-alone tool.
Associated Publications
Augspach A, Drake K, Roma L, Qian E, Lee S, Clarke D, Kumar S, Jaquet M, Gallon J, Bolis M, Triscott J, Galván J, Chen Y, Thalmann G, Kruithof-de Julio M, Theurillat J, Wuchty S, Gerstein M, Piscuoglio S, Kanadia R, Rubin M. Minor intron splicing is critical for survival of lethal prostate cancer. Molecular Cell. 2023; 83(12):1983-2002.e11.
Equipment Used
Orbitrap Fusion Lumos
Dataset Format(s)
RAW
Dataset Size
64 GB
Data Catalog Record Updated
2024-08-02