EVI1 activates tumor-promoting transcriptional enhancers in pancreatic cancer

Hwa Ryeon Kim, Juhye Yim, Hye Been Yoo, Seung Eon Lee, Sumin Oh, Sungju Jung, Chang Il Hwang, Dong Myung Shin, Tae Soo Kim, Kyung Hyun Yoo, You Sun Kim, Han Woong Lee, Jae Seok Roe

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells utilize super-enhancers (SEs) to activate the transcription factor EVI1 (ecotropic viral integration site 1) gene, resulting in activation of an EVI1-dependent transcription program conferring PDA tumorigenesis. Our data indicate that SE is the vital cis-Acting element to maintain aberrant EVI1 transcription in PDA cells. Consistent with disease progression and inferior survival outcomes of PDA patients, we further show that EVI1 upregulation is a major cause of aggressive tumor phenotypes. Specifically, EVI1 promotes anchorage-independent growth and motility in vitro and enhances tumor propagation in vivo. Mechanistically, EVI1-dependent activation of tumor-promoting gene expression programs through the stepwise configuration of the active enhancer chromatin attributes to these phenotypes. In sum, our findings support the premise that EVI1 is a crucial driver of oncogenic transcription programs in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.

Original languageEnglish
JournalNAR Cancer
Volume3
Issue number2
DOIs
StatePublished - 1 Jun 2021

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