PO-117 Role of NFE2L3 in colon cancer by regulating cancer cells proliferation

Introduction Dysfunctional transcriptional and signalling networks play a fundamental role in colorectal cancer (CRC), one of the most common and fatal malignancies worldwide. Different molecular CRC subtypes have been identified, and understanding of the underlying pathogenesis of CRC formation is crucial for predicting prognosis and treatment response. Constitutive NF-κB activation is a hallmark of colon tumour development. In this study, we aimed to unravel the cellular network governing NFE2L3 regulation and function. We report that NFE2L3 acts as a central player in a newly identified NF-kB signalling pathway that controls colon cancer cell growth. Material and methods We analysed the level of NFE2L3 in colon cancer samples extracted from patients. We compared by qPCR and immunohistochemistry the level NFE2L3 expression in normal and tumour tissues. We performed a knockdown of NFE2L3 in different colon cancer cell lines. We characterised the phenotype associated to its depletion in vitro and in vivo . Then, we used a CHIP sequencing analysis to identify the targets of NFE2L3 in our models and we validated by qPCR the direct link between NFE2L3 expression and targets discovered. Finally, by using a strategy of immunoprecipitation associated to mass spectrometry analysis, we identified potential proteins implicated in the pathway of NFE2L3 in colon cancer. Results and discussions Firstly, we observed that the expression of NFE2L3 in colon cancer samples is significantly higher compared to in normal colon tissues. Moreover, the expression of this protein directly correlated to the survival of patients and could be used as a prognostic marker in colon adenocarcinoma. After that, we depleted the expression of NFE2L3 and we observed that the proliferation of colon cancer cells was slow down. Then, we identified NF-kB pathway as a key regulator of NFE2L3 expression by regulating promoter region. Finally, we demonstrated that NFE2L3 controls the cell cycle in cancer cells by modulating the expression of negative regulators of proliferation. Conclusion Taken together, based on our observations, we propose the existence of a novel oncogenic pathway, comprising the NF–kB, NFE2L3 and cell cycle regulators, that controls cancer cell growth. Our study establishes a key role for the NFE2L3 transcription factor that regulates cell cycle progression in colon cancer cells.