Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer

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

doi:10.1016/j.celrep.2017.08.041

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer

Cell Rep. 2017 Sep 5;20(10):2408-2423. doi: 10.1016/j.celrep.2017.08.041.

Authors

Xiao Ling Li¹, Murugan Subramanian¹, Matthew F Jones¹, Ritu Chaudhary¹, Deepak K Singh², Xinying Zong², Berkley Gryder³, Sivasish Sindri³, Min Mo⁴, Aaron Schetter⁵, Xinyu Wen³, Swetha Parvathaneni⁶, Dickran Kazandjian⁵, Lisa M Jenkins⁷, Wei Tang⁸, Fathi Elloumi⁹, Jennifer L Martindale¹⁰, Maite Huarte¹¹, Yuelin Zhu¹², Ana I Robles⁵, Susan M Frier¹³, Frank Rigo¹³, Maggie Cam⁹, Stefan Ambs⁸, Sudha Sharma⁶, Curtis C Harris⁵, Mary Dasso⁴, Kannanganattu V Prasanth², Ashish Lal¹⁴

Affiliations

¹ Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
² Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
³ Oncogenomics Section, Genetics Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA.
⁴ Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
⁵ Molecular Genetics and Carcinogenesis Section, Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, MD 20892, USA.
⁶ Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC 20059, USA.
⁷ Laboratory of Cell Biology, CCR, NCI, NIH, Bethesda, MD 20892, USA.
⁸ Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, MD 20892, USA.
⁹ Office of Science and Technology Resources, CCR, NCI, NIH, Bethesda, MD 20892, USA.
¹⁰ Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
¹¹ Center for Applied Medical Research, Department of Gene Therapy and Regulation of Gene Expression, University of Navarra, 31008 Pamplona, Spain.
¹² Molecular Genetics Section, Genetics Branch, CCR, NCI, NIH, Bethesda, MD 28092, USA.
¹³ Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
¹⁴ Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].

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.

Keywords: CRC; HuR; LINC01021; LOC643401; MYBBP1A; PURPL; RP11-46C20.1; lincRNA; lncRNA; p53.

Published by Elsevier Inc.

MeSH terms

Apoptosis / genetics
Apoptosis / physiology
Cell Cycle / genetics
Cell Cycle / physiology
Cell Cycle Checkpoints / genetics
Cell Cycle Checkpoints / physiology
Cell Line
Cell Line, Tumor
Cell Proliferation / genetics
Cell Proliferation / physiology
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism
DNA-Binding Proteins
ELAV-Like Protein 1 / genetics
ELAV-Like Protein 1 / metabolism
HCT116 Cells
Humans
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Nucleocytoplasmic Transport Proteins / genetics
Nucleocytoplasmic Transport Proteins / metabolism
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / physiology
RNA-Binding Proteins
Transcription Factors
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

DNA-Binding Proteins
ELAV-Like Protein 1
MYBBP1A protein, human
Nuclear Proteins
Nucleocytoplasmic Transport Proteins
RNA, Long Noncoding
RNA-Binding Proteins
TP53 protein, human
Transcription Factors
Tumor Suppressor Protein p53

Abstract

MeSH terms

Substances

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