CDT1 (Chromatin Licensing And DNA Replication Factor 1)

Our observations demonstrate that BHLHE22 may be a promising target for TNBC therapy.

Moreover, we identified simvastatin as a potent inhibitor of CDT1, effectively inhibiting CDT1-mediated centrosome amplification and PGCC formation. In summary, our findings reveal a critical role for CDT1 in driving centrosome amplification and PGCC formation through activation of the PLK4/SASS6 axis, which subsequently contributes to therapeutic resistance and malignant progression.

Therapeutic CDK4/6 inhibitors block MCM and ORC6 loading, which we exploit to trigger mitosis with unreplicated DNA in p53-deficient cells. The CDK4/6-RB axis thus links replication licensing to proliferation, which has implications for human cell fate control and cancer therapy design.

The three-gene prognostic model effectively stratifies neuroblastoma patients by survival risk and correlates with immune microenvironment characteristics. This model has potential clinical utility for prognosis prediction and guiding personalized immunotherapy strategies in neuroblastoma.

These findings provide valuable insight into the molecular profiles of genes that play significant roles in cervical cancer for translational outcomes in diagnosis.

Notably, in vitro assays revealed that a cetacean-specific mutation M155T in the rapidly evolving gene CCND1 more effectively suppressed tumor cell proliferation and migration. Overall, our study has provided new insights into how the evolution of cell cycle-related genes balances body mass and cancer resistance in cetaceans, offering molecular support for Peto's paradox.

The failure of phase III clinical trials on the NEDD8-activating enzyme (NAE) inhibitor, MLN4924, has increased the demand for sensitive biomarkers for efficient patient selection...Our data suggest that the VOPP1-E2F1-CDT1 axis regulates the NAE inhibitor sensitivity of NSCLC cells. Furthermore, our findings provide important insights for further evaluation of VOPP1 as a potential NAE inhibitor sensitivity biomarker in clinical settings.

Arrested cells undergo apoptotic cell death. Taken together, these data strongly indicate that KLHL5 expression in CRC serves as a survival factor to strengthen the cell cycle and protect against apoptotic cell death under harsh tumor microenvironments.

Following release from proteasome inhibition, cells with elevated levels of chromatin-bound Orc6 and MCM proceed to the next replication phase as tetraploid cells. Our findings suggest that the proteasome-dependent dissociation of Orc6 after DNA replication is critical for preventing inappropriate MCM reloading and tetraploid formation.

In this study, we identified that multiple HDAC inhibitors, including fimepinostat, romidepsin and panobinostat, downregulate the levels of the RRM1, RRM2, CHK1, and WEE1 proteins in Ewing sarcoma cells, and impair DNA replication. Additionally, proteomic studies identified that HDAC inhibitors also downregulate the level of the BRD4 protein, a BET bromodomain protein that regulates both the transcriptional program of the EWS::FLI1 oncoprotein and DNA replication. Overall, these results provide novel insight into the molecular mechanisms by which HDAC inhibitors target cancer cells, regulate DNA replication, and inhibit the cellular response to DNA replication stress.

Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition.

Our study underscores the pivotal role of CDT1 in the progression from NAFLD to HCC. This finding opens new avenues for early diagnosis and targeted therapy of HCC, highlighting CDT1 as a potential therapeutic target.