Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

  1. Kevin Hu
  2. Mahmoud Ghandi
  3. Franklin W Huang  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Broad Institute of Harvard and MIT, United States

Abstract

In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1,299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.

Data availability

Telomere content estimates can be found in the supplementary materials and have been uploaded tothe Cancer Dependency Map portal (https://depmap.org/portal/).

The following previously published data sets were used
    1. DepMap
    2. Broad
    (2020) DepMap 20Q2 Public
    https://doi.org/10.6084/m9.figshare.12280541.v4.

Article and author information

Author details

  1. Kevin Hu

    Hematology/Oncology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3631-8294
  2. Mahmoud Ghandi

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Franklin W Huang

    Hematology/Oncology, University of California, San Francisco, San Francisco, United States
    For correspondence
    franklin.huang@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5447-0436

Funding

Prostate Cancer Foundation (Young Investigator Award)

  • Franklin W Huang

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

Reviewing Editor

  1. C Daniela Robles-Espinoza, International Laboratory for Human Genome Research, Mexico

Version history

  1. Received: January 2, 2021
  2. Preprint posted: January 24, 2021 (view preprint)
  3. Accepted: August 27, 2021
  4. Accepted Manuscript published: September 6, 2021 (version 1)
  5. Version of Record published: October 21, 2021 (version 2)

Copyright

© 2021, Hu 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. Kevin Hu
  2. Mahmoud Ghandi
  3. Franklin W Huang
(2021)
Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines
eLife 10:e66198.
https://doi.org/10.7554/eLife.66198

Share this article

https://doi.org/10.7554/eLife.66198

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