High-risk Human papillomaviruses (HPVs) types are associated with more than 90% of premalignant and malignant squamous lesions of the uterine cervix. The E6 oncoprotein of high-risk HPVs is a key determinant in cell transformation because it induces the degradation of the host pro-apoptotic tumor suppressor p53. E6 recruits the intracellular ubiquitin ligase E6AP and subsequently induces proteasome-dependent p53 degradation. Neither E6 nor E6AP alone interact with p53; however, the precise mechanism of the functional regulation of the E6/E6AP/p53 complex is unclear. Here, we showed that the high-risk HPV E6 proteins are ubiquitinated during E6/E6AP/p53 complex assembly and degraded by the proteasome system. Increasing p53 expression enhanced E6/E6AP/p53 assembly and facilitated E6 ubiquitination and degradation. The dominant negative mutant of p53 R175H, which does not efficiently bind E6, decreased E6 ubiquitination and increased stability. Furthermore, we showed that the ubiquitin ligase E6AP is essential for E6 ubiquitination, and downregulation of E6AP expression increased E6 stability. We also showed that p53 R175H inhibited E6-mediated p53 degradation. Consistently, the host deubiquitinating enzyme USP15 removed ubiquitin chains from E6 proteins and inhibited E6-mediated p53 degradation. Crucially, ectopic expression of either p53 R175H or USP15 promoted p53-triggered apoptosis in human cervical cancer cells. Considering the importance of ubiquitinated E6 on p53 degradation, the disruption of E6 ubiquitination represents an attractive pharmacological intervention against HPV-positive human cervical cancer.ImportanceVirtually 100% of cervical cancers are linked to HPV infection. Commercial HPV vaccines are estimated to prevent up to 90% of HPV-associated cancers, while they do not eliminate persistent HPV infections and have no effect on the progression to malignancy. Hence, the development of novel therapeutic interventions against HPV is urgently required. The HPV oncoprotein E6 binds to the intracellular E3 ubiquitin ligase E6AP and p53 resulting in the degradation of p53. In this study, we demonstrate that HPV E6 is ubiquitinated by E6AP in presence of p53. Crucially, ubiquitination of E6 is important for p53 degradation and blockage of E6 ubiquitination negatively interferes with E6-mediated p53 degradation and enhances the apoptotic effects of p53 and the cytotoxicity of DNA damage in HPV-positive cervical cancer cells. Importantly, our data suggest that the HPV oncogene E6 might be an optimal pharmacologic.
This study aims to lay a foundation for studying the regulation of microRNAs (miRNAs) in colon cancer by applying bioinformatics methods to identify miRNAs and their potential critical target genes associated with colon cancer and prognosis. Data of differentially expressed miRNAs (DEMs) and genes (DEGs) downloaded from two independent databases (TCGA and GEO) and analyzed by R software resulted in 472 DEMs and 565 DEGs in colon cancers, respectively. Next, we developed an 8-miRNA (hsa-mir-6854, hsa-mir-4437, hsa-mir-216a, hsa-mir-3677, hsa-mir-887, hsa-mir-4999, hsa-mir-34b, and hsa-mir-3189) prognostic signature for patients with colon cancer by Cox proportional hazards regression analysis. To predict the target genes of these miRNAs, we used TargetScan and miRDB. The intersection of DEGs with the target genes predicted for these eight miRNAs retrieved 112 consensus genes. GO and KEGG pathway enrichment analyses showed these 112 genes were mainly involved in protein binding, one-carbon metabolic process, nitrogen metabolism, proteoglycans in cancer, and chemokine signaling pathways. The protein-protein interaction network of the consensus genes, constructed using the STRING database and imported into Cytoscape, identified 14 critical genes in the pathogenesis of colon cancer (CEP55,
Background Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells. Main Body Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies. Conclusions Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.
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