PIGL promotes the docetaxel resistance of prostate cancer and is regulated by E3 ubiquitin ligase HUWE1.

INTRODUCTION

The mechanism related to docetaxel resistance in PCa has not been fully elucidated, and in-depth study of the specific mechanism of docetaxel resistance in PCa is of great clinical significance for the treatment of PCa.

METHODS

We explored the expression level of PIGL and HUWE1 using TCGA database and our clinical sample. CCK8 assay, Transwell assay, colony formation assay, wound-healing assay were used to explore the role of HUWE1/PIGL. Ubiquitination assay and Co-immunoprecipitation assay were used to investigate the molecular mechanism.

RESULTS

We found that both the mRNA and protein of PIGL is highly expressed in prostate cancer (PCa) and associated with poor prognosis. The protein rather than mRNA of PIGL is highly expressed in docetaxel-resistant PCa and associated with prognosis in patients receiving docetaxel-based chemotherapy. High expression level of PIGL promotes the proliferation, migration, invasion, and docetaxel resistance of PCa cells in vitro. Mass spectrometry after immunoprecipitation identified HUWE1 as a binding protein of PIGL. The protein of HUWE1 is lowly expressed in docetaxel-resistant PCa and associated with prognosis in patients receiving docetaxel-based chemotherapy. HUWE1 might be served as the E3 ubiquitin ligase of PIGL and negatively regulated the expression of PIGL protein rather than mRNA. The knockdown of HUWE1 could promote the docetaxel resistance of PCa and could be rescued by PIGL silencing.

DISCUSSION: These findings emphasized the vital role of PIGL in the progression and docetaxel resistance of PCa and the effect of the E3 ubiquitin ligase HUWE1 on regulating the protein expression of PIGL.