UCHL3 promotes cervical cancer development and metastasis by stabilizing NRF2 via deubiquitination.

ABSTRACT

Cervical cancer is one of the most lethal gynaecological malignancies in females. The deubiquitylase UCHL3 has been studied as an oncogenic factor in multiple cancers. However, the expression pattern and function profile of UCHL3 in cervical cancer hasn't been fully characterized. Here, we revealed that UCHL3 was highly expressed in cervical cancer and overexpressed UCHL3 predicted a poor survival probability in cervical cancer patients. Our findings showed that knockdown of UCHL3 inhibited cell growth, migration and invasion in cervical cancer cells while UCHL3 knockdown inhibited cervical cancer development and metastasis in vivo in mouse models. Mechanistically, co-immunoprecipitation assay showed that UCHL3 directly interacted with NRF2. Knockdown of UCHL3 decreased NRF2 expression while overexpression of UCHL3 stabilized NRF2 via deubiquitination. In addition, overexpression of UCHL3 with C92A mutation didn't affect NRF2 stability. Moreover, we revealed that overexpression of NRF2 could antagonize the function of UCHL3 knockdown in cervical cancer cells. Collectively, our findings suggest that UCHL3 promotes cervical cancer development and metastasis by stabilizing NRF2 via deubiquitination. Thus, UCHL3/NRF2 axis could be utilized to develop efficient treatments for cervical cancer patients.