1. Cancer Biology
  2. Cell Biology

PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors

  1. Kaixuan Shi
  2. Xia Yin
  3. Mei-Chun Cai
  4. Ying Yan
  5. Chenqiang Jia
  6. Pengfei Ma
  7. Shengzhe Zhang
  8. Zhenfeng Zhang
  9. Zhenyu Gu
  10. Meiying Zhang  Is a corresponding author
  11. Wen Di  Is a corresponding author
  12. Guanglei Zhuang  Is a corresponding author
  1. Shanghai Jiao Tong University, China
  2. Shanghai Cancer Institute, China
  3. GenenDesign Co Ltd, China
https://doi.org/10.7554/eLife.44306
Share this article
Cite this article
  1. Kaixuan Shi
  2. Xia Yin
  3. Mei-Chun Cai
  4. Ying Yan
  5. Chenqiang Jia
  6. Pengfei Ma
  7. Shengzhe Zhang
  8. Zhenfeng Zhang
  9. Zhenyu Gu
  10. Meiying Zhang
  11. Wen Di
  12. Guanglei Zhuang
(2019)
PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors
eLife 8:e44306.
https://doi.org/10.7554/eLife.44306
  2. Download BibTeX
  3. Download .RIS

Abstract

PAX8 is a prototype lineage-survival oncogene in epithelial ovarian cancer. However, neither its underlying pro-tumorigenic mechanisms nor potential therapeutic implications have been adequately elucidated. Here, we identified an ovarian lineage-specific PAX8 regulon using modified cancer outlier profile analysis, in which PAX8-FGF18 axis was responsible for promoting cell migration in an autocrine fashion. An image-based drug screen pinpointed that PAX8 expression was potently inhibited by small-molecules against histone deacetylases (HDACs). Mechanistically, HDAC blockade altered histone H3K27 acetylation occupancies and perturbed the super-enhancer topology associated with PAX8 gene locus, resulting in epigenetic downregulation of PAX8 transcripts and related targets. HDAC antagonists efficaciously suppressed ovarian tumor growth and spreading as single agents, and exerted synergistic effects in combination with standard chemotherapy. These findings provide mechanistic and therapeutic insights for PAX8-addicted ovarian cancer. More generally, our analytic and experimental approach represents an expandible paradigm for identifying and targeting lineage-survival oncogenes in diverse human malignancies.

Data availability

The sequencing data have been deposited in NCBI SRA database(http://www.ncbi.nlm.nih.gov/sra/) under the accession number SRP153266.

The following data sets were generated

Article and author information

Author details

  1. Kaixuan Shi

    School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Xia Yin

    School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Mei-Chun Cai

    State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Ying Yan

    Precision Oncology Lab, GenenDesign Co Ltd, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Chenqiang Jia

    School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Pengfei Ma

    School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Shengzhe Zhang

    School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Zhenfeng Zhang

    State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  9. Zhenyu Gu

    Precision Oncology Lab, GenenDesign Co Ltd, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Meiying Zhang

    School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    fudoczhang82@126.com
    Competing interests
    The authors declare that no competing interests exist.

  11. Wen Di

    School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    diwen163@163.com
    Competing interests
    The authors declare that no competing interests exist.

  12. Guanglei Zhuang

    School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    zhuanglab@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8141-5096

Funding

National Natural Science Foundation of China (81472537)

  • Guanglei Zhuang

Shanghai Municipal Commission of Health and Family Planning (20174Y0043)

  • Mei-Chun Cai

Program of Shanghai Hospital Development Center (16CR2001A)

  • Wen Di

Shanghai Jiao Tong University School of Medicine (YG2016MS51)

  • Xia Yin

The State Key Laboratory of Oncogenes and Related Genes (SB17-06)

  • Mei-Chun Cai

Shanghai Sailing Program (18YF1413200)

  • Pengfei Ma

National Key R&D Program of China (2016YFC1302900)

  • Wen Di

Science and Technology Commission of Shanghai Municipality (18441904800)

  • Wen Di

The Shanghai Institutions of Higher Learning (Eastern Scholar)

  • Guanglei Zhuang

National Natural Science Foundation of China (81672714)

  • Guanglei Zhuang

National Natural Science Foundation of China (81772770)

  • Wen Di

National Natural Science Foundation of China (81802584)

  • Meiying Zhang

National Natural Science Foundation of China (81802734)

  • Pengfei Ma

National Natural Science Foundation of China (81802809)

  • Mei-Chun Cai

Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161313)

  • Guanglei Zhuang

Shanghai Rising-Star Program (16QA1403600)

  • Guanglei Zhuang

Shanghai Municipal Commission of Health and Family Planning (2017ZZ02016,ZY(2018-2020)-FWTX-3006)

  • Wen Di

Science and Technology Commission of Shanghai Municipality (16140904401)

  • Xia Yin

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

Reviewing Editor

  1. Wilbert Zwart, Netherlands Cancer Institute, Netherlands

Ethics

Animal experimentation: The institutional animal care and use committee of Ren Ji Hospital approved all animal protocols (permit-number: m20170205) and all animal experiments were in accordance with Ren Ji Hospital policies on the care, welfare, and treatment of laboratory animals.

Version history

  1. Received: December 11, 2018
  2. Accepted: May 2, 2019
  3. Accepted Manuscript published: May 3, 2019 (version 1)
  4. Version of Record published: May 23, 2019 (version 2)

Copyright

© 2019, Shi 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.

Metrics

  • 3,005
    views
  • 526
    downloads
  • 33
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kaixuan Shi
  2. Xia Yin
  3. Mei-Chun Cai
  4. Ying Yan
  5. Chenqiang Jia
  6. Pengfei Ma
  7. Shengzhe Zhang
  8. Zhenfeng Zhang
  9. Zhenyu Gu
  10. Meiying Zhang
  11. Wen Di
  12. Guanglei Zhuang
(2019)
PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors
eLife 8:e44306.
https://doi.org/10.7554/eLife.44306

Share this article

https://doi.org/10.7554/eLife.44306

Categories and tags

Research organisms

Further reading

    1. Cancer Biology

    Recording and classifying MET receptor mutations in cancers

    Célia Guérin, David Tulasne
    Review Article

    Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.

    1. Cancer Biology
    2. Genetics and Genomics

    Convergent epigenetic evolution drives relapse in acute myeloid leukemia

    Kevin Nuno, Armon Azizi ... Ravindra Majeti
    Research Article

    Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

    1. Cancer Biology
    2. Cell Biology

    Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2

    Ibtisam Ibtisam, Alexei F Kisselev
    Short Report

    Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.