期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 10, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI151591
关键词
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资金
- US Department of Veterans Affairs [BX000792-09A2]
- Diana Princess of Wales endowed Professorship from the Robert H. Lurie Comprehensive Cancer Center
- NCI [U54 CA268084-02, CCSG P30 CA060553, CA060553]
- Cancer Center grant [NCI CA060553]
- Office of the Provost
- Office for Research
- Northwestern University Information Technology
This study identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer, which regulates the expression of IRE1? and activates stemness pathways. The findings shed light on potentially targetable pathways in cancer stem cells (CSCs) and provide valuable insights for developing new treatments.
Understanding the regulatory programs enabling cancer stem cells (CSCs) to self-renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer. Its genetic depletion diminished stemness features and reduced tumor initiation capacity. Our mechanistic studies highlight that FOXK2 directly regulated IRE1?? (encoded by ERN1) expression, a key sensor for the unfolded protein response (UPR). Chromatin immunoprecipitation and sequencing revealed that FOXK2 bound to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a catalytically inactive CRISPR/Cas9 (dCas9) diminished IRE1?? transcription. At the molecular level, FOXK2-driven upregulation of IRE1?? led to alternative XBP1 splicing and activation of stemness pathways, while genetic or pharmacological blockade of this sensor of the UPR inhibited ovarian CSCs. Collectively, these data establish what we believe is a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in CSCs.
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