USP9X/HOXA1 Contributes to the Cisplatin-Resistentance of Oral Squamous Cell Carcinoma in vitro and in vivo

Changde Sui, Ping Xia, Jinfeng Sui, Xiaoyan Wu, Xiaomei Zheng, Jianming Zhao and Xiaoli Xu

Background and Objective: The acquisition of Chemoresistance to Cisplatin (CDDP) is known as a challenge in Oral Squamous Cell Carcinoma (OSCC) therapy; but causative factors responsible for CDDP resistance in OSCC are largely ill-defined. Thus, the role and underlying mechanism of HOXA1 was explored in this study. Materials and Methods: The mRNA expression levels in normal and CDDP-resistant OSCC cells, were detected by qRT-PCR. The CCK-8, TUNEL and colony formation assays were performed to elevate the effect of HOXA1 on CDDP-resistance, cell viability and apoptosis of OSCC and CDDP-resistant OSCC (OSCC/R) cells. Western blot, Co-IP, ubiquitination and CHX analyses were carried out to uncover the regulation of USP9X on HOXA1 in CDDP-resistant OSCC, as finally confirmed by rescue experiments. The HOXA1 was highly expressed after developing into of CDDP resistance in OSCC cells. Results: A positive correlation was investigated between the expression level of HOXA1 and the IC₅₀ value of CDDP in OSCC cells. The ability against CDDP-induced cell viability impairment and apoptosis was enhanced by overexpressing HOXA1 in OSCC cells; while was impaired by silencing HOXA1 in OSCC/R cells. Mechanically, the expression of HOXA1 was regulated by the de-ubiquitination role of USP9X. Silencing USP9X led to an impairment in the CDDP resistance of OSCC cells, while this effect was reversed by overexpressing HOXA1. Conclusion: The HOXA1 contributes to the resistance of OSCC cells to CDDP, which is regulated by the deubiquitination function of USP9X.

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