PXD026949-3

PXD026949 is an original dataset announced via ProteomeXchange.

Title	Minor intron splicing efficiency increases with the development of lethal prostate cancer
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:47:23.790.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Manfred Heller
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-27 15:50:51	ID requested
1	2023-06-08 10:32:08	announced
2	2023-11-14 09:01:02	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 05:47:24	announced	2024-10-22: Updated project metadata.

10.1016/J.MOLCEL.2023.05.017;

submitter keyword: minor spliceosome, lineage plasticity, minor intron genes, U6atac,Prostate cancer

Mark A. Rubin
contact affiliation	Department for BioMedical Research (DBMR) University of Bern Murtenstrasse 35 3008 Bern Switzerland
contact email	mark.rubin@dbmr.unibe.ch
lab head
Manfred Heller
contact affiliation	Proteomics and Mass Spectrometry Core Facility, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
contact email	pmscf@dbmr.unibe.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026949
     1. Label: PRIDE project
     2. Name: Minor intron splicing efficiency increases with the development of lethal prostate cancer