Long Noncoding RNA PURPL Suppresses Basal P53 Levels and Promotes Tumorigenicity in Colorectal Cancer

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2017 Sep 7

PMID 28877474

Citations 100

Authors

Xiao Ling Li

Murugan Subramanian

Matthew F Jones

Ritu Chaudhary

Deepak K Singh

Xinying Zong

Berkley Gryder

Sivasish Sindri

Min Mo

Aaron Schetter

Xinyu Wen

Swetha Parvathaneni

Dickran Kazandjian

Lisa M Jenkins

Wei Tang

Fathi Elloumi

Jennifer L Martindale

Maite Huarte

Yuelin Zhu

Ana I Robles

Susan M Frier

Frank Rigo

Maggie Cam

Stefan Ambs

Sudha Sharma

Curtis C Harris

Mary Dasso

Kannanganattu V Prasanth

Ashish Lal

Affiliations

Soon will be listed here.

Abstract

Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.

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References

Ulitsky I, Bartel D . lincRNAs: genomics, evolution, and mechanisms. Cell. 2013; 154(1):26-46. PMC: 3924787. DOI: 10.1016/j.cell.2013.06.020. View

Marin-Bejar O, Marchese F, Athie A, Sanchez Y, Gonzalez J, Segura V . Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2. Genome Biol. 2013; 14(9):R104. PMC: 4053822. DOI: 10.1186/gb-2013-14-9-r104. View

Tani H, Nakamura Y, Ijiri K, Akimitsu N . Stability of MALAT-1, a nuclear long non-coding RNA in mammalian cells, varies in various cancer cells. Drug Discov Ther. 2012; 4(4):235-9. View

Nikulenkov F, Spinnler C, Li H, Tonelli C, Shi Y, Turunen M . Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis. Cell Death Differ. 2012; 19(12):1992-2002. PMC: 3504713. DOI: 10.1038/cdd.2012.89. View

Sanchez Y, Segura V, Marin-Bejar O, Athie A, Marchese F, Gonzalez J . Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumour suppressor signature. Nat Commun. 2014; 5:5812. PMC: 4284803. DOI: 10.1038/ncomms6812. View

Mueller A, Cichewicz M, Dey B, Layer R, Reon B, Gagan J . MUNC, a long noncoding RNA that facilitates the function of MyoD in skeletal myogenesis. Mol Cell Biol. 2014; 35(3):498-513. PMC: 4285423. DOI: 10.1128/MCB.01079-14. View

Melo C, Leveille N, Rooijers K, Wijchers P, Geeven G, Tal A . A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response. Oncogene. 2016; 35(33):4399-406. DOI: 10.1038/onc.2015.502. View

Tani H, Mizutani R, Salam K, Tano K, Ijiri K, Wakamatsu A . Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals. Genome Res. 2012; 22(5):947-56. PMC: 3337439. DOI: 10.1101/gr.130559.111. View

Hermeking H . MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer. 2012; 12(9):613-26. DOI: 10.1038/nrc3318. View

10.

Allen M, Andrysik Z, Dengler V, Mellert H, Guarnieri A, Freeman J . Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms. Elife. 2014; 3:e02200. PMC: 4033189. DOI: 10.7554/eLife.02200. View

11.

Galban S, Martindale J, Mazan-Mamczarz K, Lopez de Silanes I, Fan J, Wang W . Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells. Mol Cell Biol. 2003; 23(20):7083-95. PMC: 230328. DOI: 10.1128/MCB.23.20.7083-7095.2003. View

12.

Lal A, Kawai T, Yang X, Mazan-Mamczarz K, Gorospe M . Antiapoptotic function of RNA-binding protein HuR effected through prothymosin alpha. EMBO J. 2005; 24(10):1852-62. PMC: 1142594. DOI: 10.1038/sj.emboj.7600661. View

13.

Menendez D, Nguyen T, Freudenberg J, Mathew V, Anderson C, Jothi R . Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells. Nucleic Acids Res. 2013; 41(15):7286-301. PMC: 3753631. DOI: 10.1093/nar/gkt504. View

14.

Hunten S, Kaller M, Drepper F, Oeljeklaus S, Bonfert T, Erhard F . p53-Regulated Networks of Protein, mRNA, miRNA, and lncRNA Expression Revealed by Integrated Pulsed Stable Isotope Labeling With Amino Acids in Cell Culture (pSILAC) and Next Generation Sequencing (NGS) Analyses. Mol Cell Proteomics. 2015; 14(10):2609-29. PMC: 4597140. DOI: 10.1074/mcp.M115.050237. View

15.

Chang T, Wentzel E, Kent O, Ramachandran K, Mullendore M, Lee K . Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007; 26(5):745-52. PMC: 1939978. DOI: 10.1016/j.molcel.2007.05.010. View

16.

Lopez de Silanes I, Zhan M, Lal A, Yang X, Gorospe M . Identification of a target RNA motif for RNA-binding protein HuR. Proc Natl Acad Sci U S A. 2004; 101(9):2987-92. PMC: 365732. DOI: 10.1073/pnas.0306453101. View

17.

Bieging K, Attardi L . Deconstructing p53 transcriptional networks in tumor suppression. Trends Cell Biol. 2011; 22(2):97-106. PMC: 3541866. DOI: 10.1016/j.tcb.2011.10.006. View

18.

Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis R . CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013; 23(9):1446-61. PMC: 3759721. DOI: 10.1101/gr.152942.112. View

19.

El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J . WAF1, a potential mediator of p53 tumor suppression. Cell. 1993; 75(4):817-25. DOI: 10.1016/0092-8674(93)90500-p. View

20.

Schmitt A, Garcia J, Hung T, Flynn R, Shen Y, Qu K . An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet. 2016; 48(11):1370-1376. PMC: 5083181. DOI: 10.1038/ng.3673. View