Abstract
Therapy-induced expansion of cancer stem cells (CSCs) has been identified as one of the most critical factors contributing to therapeutic resistance, but the mechanisms of this adaptation are not fully understood. UHRF1 is a key epigenetic regulator responsible for therapeutic resistance, and controls the self-renewal of stem cells. In the present study, taxane-resistant cancer cells were established and stem-like cancer cells were expanded. UHRF1 was overexpressed in the taxane-resistant cancer cells, which maintained CSC characteristics. UHRF1 depletion overcame taxane resistance in vitro and in vivo. Additionally, FOXM1 has been reported to play a role in therapeutic resistance and the self-renewal of CSCs. FOXM1 and UHRF1 are highly correlated in prostate cancer tissues and cells, FOXM1 regulates CSCs by regulating uhrf1 gene transcription in an E2F-independent manner, and FOXM1 protein directly binds to the FKH motifs at the uhrf1 gene promoter. This present study clarified a novel mechanism by which FOXM1 controls CSCs and taxane resistance through a UHRF1-mediated signaling pathway, and validated FOXM1 and UHRF1 as two potential therapeutic targets to overcome taxane resistance.
Highlights
Taxane, including paclitaxel (Taxol), and docetaxel (Taxotere), has been widely used in cancer chemotherapy
These results showed that the expansion of the cancer stem cells (CSCs) subpopulation is a critical factor in the development of taxane resistance
We found that FOXM1 is overexpressed in paclitaxel-resistant cancer cells, and FOXM1 depletion overcame the paclitaxelresistance by decreasing drug efflux[3]
Summary
Taxane, including paclitaxel (Taxol), and docetaxel (Taxotere), has been widely used in cancer chemotherapy. Taxanes bind to β-tubulin, thereby reducing depolymerization. The molecular mechanisms by which cancer cells develop taxane resistance are not fully understood. Taxane resistance is subclassified as innate resistance and acquired resistance. Acquired resistance results from the increased expression of drug efflux proteins such as ATP-binding cassette (ABC transporters)[3], the altered expression and function of certain tubulin isotypes[4], and the deregulation of Bcl-2 molecules[5,6]. Taxanes induced the expansion of stem-cell-like cancer cells, resulting in the development of taxane resistance and cancer relapse[7]
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