PHAROH lncRNA regulates Myc translation in hepatocellular carcinoma via sequestering TIAR

  1. Allen T Yu
  2. Carmen Berasain
  3. Sonam Bhatia
  4. Keith Rivera
  5. Bodu Liu
  6. Frank Rigo
  7. Darryl J Pappin
  8. David L Spector  Is a corresponding author
  1. Cold Spring Harbor Laboratory, United States
  2. University of Navarra, Spain
  3. Ionis Pharmaceutials, United States

Abstract

Hepatocellular carcinoma, the most common type of liver malignancy, is one of the most lethal forms of cancer. We identified a long non-coding RNA, Gm19705, that is over-expressed in hepatocellular carcinoma and mouse embryonic stem cells. We named this RNA Pluripotency and Hepatocyte Associated RNA Overexpressed in HCC, or PHAROH. Depletion of PHAROH impacts cell proliferation and migration, which can be rescued by ectopic expression of PHAROH. RNA-seq analysis of PHAROH knockouts revealed that a large number of genes with decreased expression contain a Myc motif in their promoter. MYC is decreased at the protein level, but not the mRNA level. RNA-antisense pulldown identified nucleolysin TIAR, a translational repressor, to bind to a 71-nt hairpin within PHAROH, sequestration of which increases MYC translation. In summary, our data suggest that PHAROH regulates MYC translation by sequestering TIAR and as such represents a potentially exciting diagnostic or therapeutic target in hepatocellular carcinoma.

Data availability

RNA-seq data has been uploaded to GEO: GSE167316

The following data sets were generated

Article and author information

Author details

  1. Allen T Yu

    Gene Expression, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  2. Carmen Berasain

    Hepatology Program, University of Navarra, Pamplona, Spain
    Competing interests
    No competing interests declared.
  3. Sonam Bhatia

    Gene Expression, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0124-2621
  4. Keith Rivera

    Gene Expression, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  5. Bodu Liu

    Gene Expression, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  6. Frank Rigo

    Antisense, Ionis Pharmaceutials, Carlsbad, United States
    Competing interests
    No competing interests declared.
  7. Darryl J Pappin

    Gene Expression, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  8. David L Spector

    Gene Expression, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    For correspondence
    spector@cshl.edu
    Competing interests
    David L Spector, D.L.S. is a consultant to and receives research reagents from Ionis Pharmaceuticals..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3614-4965

Funding

National Cancer Institute (5PO1CA013106-Project 3)

  • David L Spector

National Cancer Institute (5F31CA220997)

  • Allen T Yu

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 experimental protocols were approved (CEEA 062-16) and performed according to the guidelines of the Ethics Committee for Animal Testing of the University of Navarra.

Human subjects: The Human Research Review Committee of the University of Navarra (CEI 47/2015) approved the study and human samples were provided by the Biobank of the University of Navarra. The biobank obtained an informed consent and consent to publish from each patient and codified samples were provided to the researchers. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Samples were processed following standard operating procedures approved by the Ethical and Scientific Committees. Liver samples from healthy patients were collected from individuals with normal or minimal changes in the liver at surgery of digestive tumors or from percutaneous liver biopsy performed because of mild alterations of liver function. Samples for cirrhotic liver and HCC were obtained from patients undergoing partial hepatectomy and/or liver transplantation.

Reviewing Editor

  1. Robert H Singer, Albert Einstein College of Medicine, United States

Publication history

  1. Received: March 10, 2021
  2. Accepted: May 2, 2021
  3. Accepted Manuscript published: May 18, 2021 (version 1)
  4. Accepted Manuscript updated: May 20, 2021 (version 2)
  5. Version of Record published: May 28, 2021 (version 3)

Copyright

© 2021, Yu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Allen T Yu
  2. Carmen Berasain
  3. Sonam Bhatia
  4. Keith Rivera
  5. Bodu Liu
  6. Frank Rigo
  7. Darryl J Pappin
  8. David L Spector
(2021)
PHAROH lncRNA regulates Myc translation in hepatocellular carcinoma via sequestering TIAR
eLife 10:e68263.
https://doi.org/10.7554/eLife.68263

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