PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors
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.
-
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.
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
-
- 3,348
- views
-
- 561
- downloads
-
- 37
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
-
- Cancer Biology
- Immunology and Inflammation
In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.