A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells

Abstract

Long noncoding RNAs (lncRNAs) are often associated with polysomes, indicating coding potential. However, only a handful of endogenous proteins encoded by putative lncRNAs have been identified and assigned a function. Here, we report the discovery of a putative gastrointestinal tract-specific lncRNA (LINC00675) that is regulated by the pioneer transcription factor FOXA1 and encodes a conserved small protein of 79 amino acids which we termed FORCP (FOXA1-Regulated Conserved Small Protein). FORCP transcript is undetectable in most cell types but is abundant in well-differentiated colorectal cancer (CRC) cells where it functions to inhibit proliferation, clonogenicity and tumorigenesis. The epitope-tagged and endogenous FORCP protein predominantly localizes to the endoplasmic reticulum (ER). In response to ER stress, FORCP depletion results in decreased apoptosis. Our findings on the initial characterization of FORCP demonstrate that FORCP is a novel, conserved small protein encoded by a mis-annotated lncRNA that regulates apoptosis and tumorigenicity in well-differentiated CRC cells.

Data availability

RNA-seq and ChIP-seq data related to this manuscript has been submitted to GEO under accession number GSE140536.

The following data sets were generated

Article and author information

Author details

  1. Xiao Ling Li

    Regulatory RNAs and Cancer Section Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  2. Lőrinc Pongor

    Developmental Therapeutics Branch, CCR, NCI, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  3. Wei Tang

    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  4. Sudipto Das

    Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc.,, National Institutes of Health, Frederick, United States
    Competing interests
    No competing interests declared.
  5. Bruna R Muys

    Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  6. Matthew F Jones

    Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  7. Sarah B Lazar

    Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  8. Emily A Dangelmaier

    Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  9. Corrine CR Hartford

    Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  10. Ioannis Grammatikakis

    Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  11. Qinyu Hao

    Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7059-7741
  12. Qinyu Sun

    Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
  13. Aaron Schetter

    Molecular Genetics and Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  14. Jennifer L Martindale

    Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, United States
    Competing interests
    No competing interests declared.
  15. BinWu Tang

    Laboratory of Cancer Biology and Genetics, CCR, NCI, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  16. Lisa M Jenkins

    Laboratory of Cell Biology, CCR, NCI, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  17. Ana I Robles

    Molecular Genetics and Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  18. Robert L Walker

    Molecular Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  19. Stefan Ambs

    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  20. Raj Chari

    Genome Modification Core, Frederick National Lab for Cancer Research, NCI, NIH, Bethesda, United States
    Competing interests
    No competing interests declared.
  21. Svetlana A Shabalina

    National Center for Biotechnology Information, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  22. Myriam Gorospe

    Intramural Research Program, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    No competing interests declared.
  23. Perwez S Hussain

    Pancreatic Cancer Unit at the Laboratory of Human Carcinogenesis, CCR, NCI, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  24. Curtis C Harris

    Pancreatic Cancer Unit at the Laboratory of Human Carcinogenesis, CCR, NCI, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  25. Paul S Meltzer

    Molecular Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  26. Kannanganattu V Prasanth

    Cell and Developmental Biology, University of Illinois at Urbana Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4587-8362
  27. Mirit I Aladjem

    Developmental Therapeutics Branch, CCR, NCI, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  28. Thorkell Andresson

    Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc.,, National Institutes of Health, Frederick, United States
    Competing interests
    No competing interests declared.
  29. Ashish Lal

    Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
    For correspondence
    ashish.lal@nih.gov
    Competing interests
    Ashish Lal, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4299-8177

Funding

National Institutes of Health (ZIA BC 011646)

  • Ashish Lal

National Science Foundation (NSF-EAGER)

  • Kannanganattu V Prasanth

National Institutes of Health (R01 GM132458)

  • Kannanganattu V Prasanth

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal protocols (protocol number LC-070-3) were approved by the National Cancer Institute Animal Care and Use Committee following AALAAC guidelines and policies.

Reviewing Editor

  1. Maureen E Murphy, The Wistar Institute, United States

Version history

  1. Received: November 18, 2019
  2. Accepted: October 27, 2020
  3. Accepted Manuscript published: October 28, 2020 (version 1)
  4. Version of Record published: November 18, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Xiao Ling Li
  2. Lőrinc Pongor
  3. Wei Tang
  4. Sudipto Das
  5. Bruna R Muys
  6. Matthew F Jones
  7. Sarah B Lazar
  8. Emily A Dangelmaier
  9. Corrine CR Hartford
  10. Ioannis Grammatikakis
  11. Qinyu Hao
  12. Qinyu Sun
  13. Aaron Schetter
  14. Jennifer L Martindale
  15. BinWu Tang
  16. Lisa M Jenkins
  17. Ana I Robles
  18. Robert L Walker
  19. Stefan Ambs
  20. Raj Chari
  21. Svetlana A Shabalina
  22. Myriam Gorospe
  23. Perwez S Hussain
  24. Curtis C Harris
  25. Paul S Meltzer
  26. Kannanganattu V Prasanth
  27. Mirit I Aladjem
  28. Thorkell Andresson
  29. Ashish Lal
(2020)
A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells
eLife 9:e53734.
https://doi.org/10.7554/eLife.53734

Share this article

https://doi.org/10.7554/eLife.53734

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