Altered RNA splicing by mutant p53 activates oncogenic RAS signaling in pancreatic cancer Journal Article
| Authors: | Escobar-Hoyos, L. F.; Penson, A.; Kannan, R.; Cho, H.; Pan, C. H.; Singh, R. K.; Apken, L. H.; Hobbs, G. A.; Luo, R.; Lecomte, N.; Babu, S.; Pan, F. C.; Alonso-Curbelo, D.; Morris, J. P. 4th; Askan, G.; Grbovic-Huezo, O.; Ogrodowski, P.; Bermeo, J.; Saglimbeni, J.; Cruz, C. D.; Ho, Y. J.; Lawrence, S. A.; Melchor, J. P.; Goda, G. A.; Bai, K.; Pastore, A.; Hogg, S. J.; Raghavan, S.; Bailey, P.; Chang, D. K.; Biankin, A.; Shroyer, K. R.; Wolpin, B. M.; Aguirre, A. J.; Ventura, A.; Taylor, B.; Der, C. J.; Dominguez, D.; Kümmel, D.; Oeckinghaus, A.; Lowe, S. W.; Bradley, R. K.; Abdel-Wahab, O.; Leach, S. D. |
| Article Title: | Altered RNA splicing by mutant p53 activates oncogenic RAS signaling in pancreatic cancer |
| Abstract: | Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC. © 2020 Escobar-Hoyos et al. reveal that mutant p53 can regulate RNA splicing to increase KRAS activity in pancreatic cancer. Targeting this splicing axis in mutant p53 pancreatic cancer reduces tumor growth and KRAS signaling, indicating a putative therapeutic strategy for this hard-to-treat cancer. © 2020 |
| Keywords: | signal transduction; cancer survival; controlled study; human cell; promoter region; exon; nonhuman; protein motif; cell proliferation; animal cell; mouse; animal tissue; gene targeting; gene overexpression; tumor volume; carboxy terminal sequence; protein protein interaction; animal experiment; animal model; cohort analysis; genetic association; genotype; enzyme activity; protein p53; oncogenes; dna; nucleotide sequence; alternative rna splicing; mitogen activated protein kinase 1; mitogen activated protein kinase 3; cellular distribution; pancreas adenocarcinoma; guanosine triphosphatase activating protein; gene silencing; pancreatic cancer; alanine; kras; spliceosome; dna binding; rna processing; k ras protein; cell activation; rna splicing; p53; stable expression; proline; cancer gene therapy; cytosine; cofilin; antisense oligonucleotide; antisense therapy; gene knockdown; human; female; priority journal; article; sf3b1; rna sequencing; organoid; gap17; gtpase signaling; hnrnpk; splicing inhibitors; enzymatic hydrolysis |
| Journal Title: | Cancer Cell |
| Volume: | 38 |
| Issue: | 2 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2020-08-10 |
| Start Page: | 198 |
| End Page: | 211.e8 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2020.05.010 |
| PUBMED: | 32559497 |
| PROVIDER: | scopus |
| PMCID: | PMC8028848 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
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