Spartin Promotes Smurf1-Mediated Ubiquitination Modification of YWHAZ to Inhibit Cisplatin Resistance in Ovarian Cancer

Cisplatin (DDP) remains the commonly used chemotherapeutic drug for ovarian Cancer (OV); however, DDP resistance poses a great challenge to the outcomes of patients. This work investigated the biological function and mechanism of Spartin in DDP resistance of OV. The growth and Apoptosis of DDP-resistant OV cells were assessed by CCK-8, colony formation, and flow cytometry, respectively. Autolysosome fusion was observed by immunofluorescent staining of LC3 and LAMP2. The interaction between E3 Ligase Smurf1 and YWHAZ or Spartin protein, and the ubiquitination level of YWHAZ were determined by Co-IP assay. Expression levels of Autophagy or apoptosis-related markers were measured by RT-qPCR, western blotting, and immunohistochemistry. DDP resistance was assessed by xenograft tumor experiments in vivo. We found that Spartin expression was lower, while YWHAZ expression was higher in DDP-resistant OV samples and cells. Lower expression of Spartin indicated a poorer survival rate of OV patients. In addition, overexpression of Spartin sensitized OV cells to DDP and repressed Autophagy. Moreover, Spartin bound to Smurf1 to promote Smurf1-mediated ubiquitination and degradation of YWHAZ, restraining Autophagy and DDP resistance. Overexpression of YWHAZ counteracted the effects of Spartin against DDP resistance by promoting Autophagy. In conclusion, Spartin-induced Smurf1-mediated ubiquitination modification of YWHAZ to inactivate Autophagy, thereby increasing the sensitivity of OV cells to DDP. Our findings suggest that Spartin-combined therapy might act as an effective approach to fight against DDP resistance in OV.

Spartin; YWHAZ; autophagy; cisplatin resistance; ovarian cancer; ubiquitination.