Proteomics

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


ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Prostate Gland

SUBMITTER: Manfred Heller  

LAB HEAD: Mark A. Rubin

PROVIDER: PXD026949 | Pride | 2023-06-08

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20200108_16_PM154_rep2_NT_AA_i01.raw Raw
20200108_16_PM154_rep2_NT_AA_i02.raw Raw
20200108_1_C42_rep1_NT_AA_i01.raw Raw
20200108_1_C42_rep1_NT_AA_i02.raw Raw
20200108_23_22RV1_rep3_SCR_AA_i01.raw Raw
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