Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors
Kevin M. Elias, … , Myles Brown, Ronny Drapkin
Kevin M. Elias, … , Myles Brown, Ronny Drapkin
Published August 18, 2016
Citation Information: JCI Insight. 2016;1(13):e87988. https://doi.org/10.1172/jci.insight.87988.
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Research Article Oncology

Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors

Abstract

Regulation of lineage-restricted transcription factors has been shown to influence malignant transformation in several types of cancer. Whether similar mechanisms are involved in ovarian cancer pathogenesis is unknown. PAX8 is a nuclear transcription factor that controls the embryologic development of the Müllerian system, including the fallopian tubes. Recent studies have shown that fallopian tube secretory epithelial cells (FTSECs) give rise to the most common form of ovarian cancer, high-grade serous ovarian carcinomas (HGSOCs). We designed the present study in order to understand whether changes in gene expression between FTSECs and HGSOCs relate to alterations in PAX8 binding to chromatin. Using whole transcriptome shotgun sequencing (RNA-Seq) after PAX8 knockdown and ChIP-Seq, we show that FTSECs and HGSOCs are distinguished by marked reprogramming of the PAX8 cistrome. Genes that are significantly altered between FTSECs and HGSOCs are enriched near PAX8 binding sites. These sites are also near TEAD binding sites, and these transcriptional changes may be related to PAX8 interactions with the TEAD/YAP1 signaling pathway. These data suggest that transcriptional changes after transformation in ovarian cancer are closely related to epigenetic remodeling in lineage-specific transcription factors.

Authors

Kevin M. Elias, Megan M. Emori, Thomas Westerling, Henry Long, Anna Budina-Kolomets, Fugen Li, Emily MacDuffie, Michelle R. Davis, Alexander Holman, Brian Lawney, Matthew L. Freedman, John Quackenbush, Myles Brown, Ronny Drapkin

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Figure 1

Impact of PAX8 knockdown on cell line transcriptomes.

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Impact of PAX8 knockdown on cell line transcriptomes. Benign fallopian t...
Benign fallopian tube secretory epithelial cells (FTSEC, designated FT33, FT194, and FT246) and high-grade serous ovarian cancer cell lines (HGSOC, known as OVSAHO, KURAMOCHI, and JHOS4) were subjected to PAX8 siRNA knockdown followed by RNA-Seq. (A) K-means clustering of top 100 most differentially expressed transcripts for each cell line. There are 5–6 transcriptome results for each cell line (untransfected control, nontargeting control, and 3–4 siRNA replicates). (B) From the same dataset, expression of the PAX homologs in each cell line.