PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

ABSTRACT: Protein phosphatase 2A (PP2A) is a promiscuous enzyme that acts on many aspects of cellular physiology. It remains unclear however, which of the cellular processes are most perturbed upon inhibition of PP2A and how such perturbations could be exploited therapeutically. Here, we report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to phosphatase 2A (PP2A) inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. These phosphorylation changes endow LB-100 treated colorectal adenocarcinoma cells with differential splicing patterns. Over 1000 exon skipping and intron retention events were enriched in PP2A-inhibited cells affecting the splicing of regulators of genomic integrity and DNA damage response. Finally, alternatively spliced transcripts downstream to LB-100 are predicted to be a source of neoantigens that can improve cancer treatment outcomes in response to immune checkpoint modulators. Collectively, our findings provide a potential explanation for the pre-clinical and clinical observations that inhibition of PP2A results in increased sensitivity of cancer cells to immune checkpoint blockade and DNA damaging agents.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colorectal Cancer Cell Line, Epithelial Cell

DISEASE(S): Colorectal Cancer

SUBMITTER: Onno Bleijerveld  

LAB HEAD: Onno B

PROVIDER: PXD043658 | Pride | 2024-06-16

REPOSITORIES: Pride