Abstract 85P
Background
5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the Zinc finger protein 334 (ZNF334) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between ZNF334 and 5-FU resistance in CRC remains unclear.
Methods
We conducted a comprehensive investigation into the influence and underlying mechanism of ZNF334 on the sensitivity to 5-FU chemotherapy using 3D organoid, cellular, and animal models of colorectal cancer.
Results
Here, we revealed that ZNF334 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring ZNF334 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting G2/M phase arrest. In addition, ZNF334 increases the stability of CDK1 and p-CDK1 (Tyr15and Thr14, inhibitory phosphorylation site), while promoting the ubiquitination degradation of cyclin B1. Mechanistically, we showed that CDK1-cyclinB1 inactivation was a key determinant in enhancing the sensitivity of 5-FU. ZNF334 activates the deubiquitinating enzyme UCHL1. Then, on the one hand, ZNF334 mediates UCHL1 to increase the stability of CDK1 and p-CDK1, on the other hand, ZNF334 mediates UCHL1 to recruit E3 ligase CRL2-ZYG11A to promote ubiquitination degradation of cyclin B1. This results in the inactivation of CDK1-cylin B1, which induces cell G2/M phase arrest, and ultimately increases the sensitivity of 5-FU.
Conclusions
Taken together, our findings suggest for the first time that ZNF334 increases the sensitivity of CRC to 5-FU treatment by Ubiquitination Modification of CDK1-cylinB1. ZNF334 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.
Clinical trial identification
N/A
Editorial acknowledgement
N/A
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.