Chemotherapy-induced distal enhancers drive transcriptional programs to maintain the chemoresistant state in ovarian cancer

Stephen Shang, Jiekun Yang, Amir A. Jazaeri, Alexander James Duval, Turan Tufan, Natasha Lopes Fischer, Mouadh Benamar, Fadila Guessous, Inyoung Lee, Robert M. Campbell, Philip J. Ebert, Tarek Abbas, Charles N. Landen, Analisa Difeo, Peter C. Scacheri, Mazhar Adli*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharma-cologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers. Significance: Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.

Original languageEnglish (US)
Pages (from-to)4599-4611
Number of pages13
JournalCancer Research
Volume79
Issue number18
DOIs
StatePublished - Sep 15 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Chemotherapy-induced distal enhancers drive transcriptional programs to maintain the chemoresistant state in ovarian cancer'. Together they form a unique fingerprint.

  • Cite this

    Shang, S., Yang, J., Jazaeri, A. A., Duval, A. J., Tufan, T., Fischer, N. L., Benamar, M., Guessous, F., Lee, I., Campbell, R. M., Ebert, P. J., Abbas, T., Landen, C. N., Difeo, A., Scacheri, P. C., & Adli, M. (2019). Chemotherapy-induced distal enhancers drive transcriptional programs to maintain the chemoresistant state in ovarian cancer. Cancer Research, 79(18), 4599-4611. https://doi.org/10.1158/0008-5472.CAN-19-0215