Knockdown of USP8 inhibits prostate cancer cell growth, proliferation, and metastasis and promotes docetaxel’s activity by suppressing the NF-kB signaling pathway

Abstract

Ubiquitin-specific protease 8 (USP8) has been recently reported to be involved in tumorigenesis. Prostate cancer (PCa) is the most diagnosed malignancy among men, but USP8’s role in PCa is not yet investigated comprehensively. Therefore, the PCa cell lines DU145 and PC3 were transfected with USP8 siRNA or overexpressing vector together with or without docetaxel. The silencing USP8 and docetaxel treatment reduced cell viability and migration and promoted apoptosis. In contrast, USP8 knockdown was found to enhance docetaxel antitumor activity. In contrast, increased cell viability and migration were noticed upon USP8 overexpression, thereby decreasing apoptosis and suppressing docetaxel antitumor activity. Notably, although EGFR, PI3K, and NF-kB were found to be increased in both USP8 overexpression and docetaxel treatment, it significantly attenuated the effects in USP8 silencing followed by with or without docetaxel. Although EGFR silencing decreased PI3K and NF-kB activation, overexpression of USP8 was shown to counteract SiEGFR’s effects on NF-kB signaling by increasing PI3K expression. Our findings revealed that USP8 plays an oncogenic role in PCa and can suppress docetaxel activity. Additionally, as EGFR/PI3K/NF-kB was previously reported to develop docetaxel resistance, the combination treatment of USP8 knockdown with docetaxel might be a potential PCa therapeutic.

GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

“…NF-kB has been shown to mediate EMT process in colorectal cancer [40], gastric cancer [41] and TNBC [42]. Moreover, the activation of NF-kB was also closely associated with the metastatic progression in several types of cancer [43][44][45][46][47][48]. In breast cancer, NF-kB played a pivotal role in triggering cancer initiation, growth, metastasis and resistance to chemotherapy [49].…”

GRK6 promotes triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

“…NF-κB has been shown to mediate EMT process in colorectal cancer [40], gastric cancer [41] and TNBC [42]. Moreover, the activation of NF-κB was also closely associated with the metastatic progression in several types of cancer [43][44][45][46][47][48]. In breast cancer, NF-κB played a pivotal role in triggering cancer initiation, growth, metastasis and resistance to chemotherapy [49].…”

Comprehensive Molecular Characterization of a Large Series of Calcified Chondroid Mesenchymal Neoplasms Widening Their Morphologic Spectrum

“…The upregulated or mutated USP8 becomes hyperactivated and stabilizes numerous oncogenes or proto-oncogenes leading to cancer progression and survival by activating multiple signaling pathways. 41 Recently USP8 fusion gene was reported in a childhood leukemia. 42 The involvement of PDGFRA as the 5′partner of a fusion may help to sustain a deregulated kinase activity.…”

“…USP8 is a deubiquitinating enzyme in the family of ubiquitin-specific proteases (USPs), which can remove ubiquitin from the substrate and protect the substrate from degradation. The upregulated or mutated USP8 becomes hyperactivated and stabilizes numerous oncogenes or proto-oncogenes leading to cancer progression and survival by activating multiple signaling pathways 41 . Recently USP8 fusion gene was reported in a childhood leukemia 42 .…”