Abstract
Background: The current standard therapeutic approach for colorectal cancer (CRC) is surgical operation and oxaliplatin (OXA)-based neoadjuvant chemotherapy. However, the acquisition of oxaliplatin resistance leads to an unfavorable prognosis in CRC. Therefore, there is an urgent need to elucidate the underlying mechanisms of oxaliplatin resistance. Methods: RNA-sequencing (RNA-seq) analysis of OXA-resistant CRC cell line was used to identify the driver of OXA resistance. Function of KIAA1429 in OXA-resistance was validated by in vivo and in vitro experiments. The underlying mechanism was investigated by Immunoprecipitation-Mass Spectrometry (IP-MS), Co-Immunoprecipitation (Co-IP), Immunofluorescence (IF), RNA immunoprecipitation (RIP) and RNA-seq. Results: KIAA1429 is significantly upregulated in oxaliplatin-resistant cell lines. However, we found that the expression level of KIAA1429 is not associated with the efficacy of neoadjuvant chemotherapy in colorectal cancer, indicating that the function of KIAA1429 is not solely determined by its expression level. We discovered that KIAA1429 exhibits differential nuclear and cytoplasmic distribution in colorectal cancer samples and that high cytoplasmic expression of KIAA1429 is associated with poor response to chemotherapy. Further investigation revealed that the nuclear-cytoplasmic distribution of KIAA1429 is regulated by BRAF-mediated phosphorylation. In vitro and in vivo experiments indicated that BRAF-mediated phosphorylation of KIAA1429 promotes oxaliplatin resistance by facilitating its aggregation in the cytoplasm. Mechanistically, we found that cytoplasmic KIAA1429 promotes WNT pathway activation by binding and stabilizing FZD7, thereby further enhancing cancer stemness and oxaliplatin resistance. Conclusions: This study elucidates the unique role of KIAA1429 phosphorylation in regulating its nuclear localization and function, offering novel insights into the mechanisms underlying OXA-resistance in CRC.