Abstract
Cancer stem cells (CSC) represent a population of cancer cells responsible for tumor initiation, chemoresistance, and metastasis. Here, we identified the H3K79 methyltransferase disruptor of telomeric silencing-1-like (DOT1L) as a critical regulator of selfrenewal and tumor initiation in ovarian CSCs. DOT1 L was upregulated in ovarian CSCs versus non-CSCs. shRNA-mediated DOT1 L knockdown decreased the aldehyde dehydrogenase (ALDH)+ cell population, impaired the tumor initiation capacity (TIC) of ovarian CSCs, and blocked the expression of stemnessassociated genes. Inhibition of DOT1L's methyltransferase activity by the small-molecule inhibitor (DOT1Li) EPZ-5676 also effectively targeted ovarian CSCs. Integrated RNA-sequencing analyses of ovarian cancer cells in which DOT1 L was knocked down versus control cells and of ovarian CSCs versus non-CSCs, identified Wnt signaling as a shared pathway deregulated in both CSCs and in DOT1L-deficient ovarian cancer cells. β-catenin, a key transcription factor regulated by Wnt, was downregulated in ovarian cancer cells in which DOT1L was knocked down and upregulated in DOT1 L overexpressing ovarian cancer cells. Chromatin immunoprecipitation (ChIP) revealed enrichment of the H3K79Me3 mark at the β-catenin promoter, suggesting that its transcription is regulated by DOT1L. Our results suggest that DOT1 L is critical for the selfrenewal and TIC of ovarian CSCs by regulating β-catenin signaling. Targeting DOT1 L in ovarian cancer could be a new strategy to eliminate CSCs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 140-154 |
| Number of pages | 15 |
| Journal | Molecular Cancer Research |
| Volume | 21 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2023 |
Funding
D. Matei reports grants from US Department of Veterans Affairs and grants from National Cancer Institute during the conduct of the study; personal fees from GSK, AstraZeneca, Seagen, personal fees and other support from Eisai, as well as grants from Abbvie, Pinotbio, and grants and personal fees from GOG Foundation outside the submitted work. No disclosures were reported by the other authors. This research was supported by funding from the US Department of Veterans Affairs (BX000792–09A2), NCI U54 CA268084–02, and the Diana Princess of Wales endowed Professorship from the Lurie Cancer Center (to D. Matei). Tumor specimens were procured through the Tissue Pathology Core and sequencing was performed in the NUSeq Core supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Flow cytometry analyses were performed in the Northwestern University—Flow Cytometry Core Facility supported by Cancer Center Support Grant NCI CA060553. Imaging of TMA was performed in the Center for Advanced Microscopy/Nikon Imaging Center (CAM) at North-western University supported by NCI CA060553. This research was supported in part through the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University that is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology.
ASJC Scopus subject areas
- General Medicine
