Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.
Kevin M
KM
Elias
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA.
Megan M
MM
Emori
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Thomas
T
Westerling
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Henry
H
Long
Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Anna
A
Budina-Kolomets
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Fugen
F
Li
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Emily
E
MacDuffie
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.
Michelle R
MR
Davis
Computational Biology and Functional Genomics Laboratory, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts, USA.
Alexander
A
Holman
Computational Biology and Functional Genomics Laboratory, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts, USA.
Brian
B
Lawney
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Matthew L
ML
Freedman
Computational Biology and Functional Genomics Laboratory, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts, USA.
John
J
Quackenbush
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Myles
M
Brown
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.; Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Ronny
R
Drapkin