PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors
- Shanghai Jiao Tong University, China
- Shanghai Cancer Institute, China
- GenenDesign Co Ltd, China
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.
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RNAseq of ovarian cancer cell lines: HDAC inhibitors,sgPAX8 treatmentNCBI Sequence Read Archive, SRP153266.
Article and author information
Author details
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.
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.
Reviewing Editor
- Wilbert Zwart, Netherlands Cancer Institute, Netherlands
Publication history
- Received: December 11, 2018
- Accepted: May 2, 2019
- Accepted Manuscript published: May 3, 2019 (version 1)
- 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.
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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
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