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Prostate cancer (PCa) is a leading malignancy in men, and understanding its molecular mechanisms is crucial for advancing therapeutic strategies. Ubiquitination, a key post-translational modification, regulates protein degradation and signaling, playing a vital role in cancer progression. This study focuses on HECTD4, a HECT-type E3 ubiquitin ligase, to identify its ubiquitination targets and understand its role in PCa.

HECTD4 knockdown was performed in LNCaP, PC-3, and DU145 PCa cell lines. A combination of semi-quantitative PCR and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify proteins with altered expression and ubiquitination profiles. Gene ontology analysis, pathway analysis, and a proliferation assay were conducted to explore the biological significance of HECTD4.

We identified 1,605 downregulated and 1,736 upregulated proteins upon HECTD4 knockdown. Key proteins involved in tumor suppression and cell cycle regulation, such as NUSAP1, CDK6, and MED13L, were ubiquitinated by HECTD4. Functional annotations revealed that these targets are associated with critical pathways, including phosphoinositide 3-kinase (PI3K)-AKT, Ras-mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR), as well as immune infiltration, drug response, and survival analysis.

HECTD4 regulates protein stability and activation through ubiquitination, impacting cell cycle progression, tumor suppression, and immune response in PCa. These findings suggest that HECTD4 is a promising therapeutic target, with potential applications in drug development aimed at disrupting oncogenic signaling and enhancing treatment efficacy.