DPPA3-HIF1a axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE207862 | GEO | 2023/08/02
REPOSITORIES: GEO
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Project description:Tumor relapse is linked to rapid chemoresistance and represents a bottleneck for cancer therapy success. Engagement of a reduced proliferation state is a non-mutational mechanism exploited by cancer cells to bypass therapy-induced cell death. Through combining pulse-chase experiments in engineered CRC cells and transcriptomic analyses, we identified DPPA3 as a master regulator of slow-cycling phenotype in CRC. We find that DPPA3 stabilizes HIF1a even in normoxia thus limiting nuclear CCNB1 levels and represses DNA replication and cell cycle programs resulting in a slow cell-cycle phenotype. Down-regulation of HIF1a partially restores a chemosensitive proliferative phenotype in DPPA3-overexpressing cancer cells. In cohorts of patient samples, we find that DPPA3 is a predictive biomarker of CRC chemotherapeutic resistance and tumor relapse. Our work demonstrates that slow-cycling cancer cells exploit a DPPA3/HIF1a axis to support tumor persistence under therapeutic stress and provides key insights on the molecular regulation of tumor cell slow-cycliness and chemoresistance. This dataset comprises DNA methylation data of SW1222 CRC cells subjected to DPPA3 overexpression for 5 days.
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Project description:DPPA3-HIF1a axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype
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