Abstract
Paclitaxel is widely used as a first-line chemotherapeutic drug for patients with ovarian cancer and other solid cancers, but drug resistance occurs frequently, resulting in ovarian cancer still presenting as the highest lethality among all gynecological tumors. Here, using DIGE quantitative proteomics, we identified UBC13 as down-regulated in paclitaxel-resistant ovarian cancer cells, and it was further revealed by immunohistochemical staining that UBC13 low-expression was associated with poorer prognosis and shorter survival of the patients. Through gene function experiments, we found that paclitaxel exposure induced UBC13 down-regulation, and the enforced change in UBC13 expression altered the sensitivity to paclitaxel. Meanwhile, the reduction of UBC13 increased DNMT1 levels by attenuating its ubiquitination, and the up-regulated DNMT1 enhanced the CHFR promoter DNA methylation levels, leading to a reduction of CHFR expression, and an increased in the levels of Aurora A. Our findings revealed a novel function for UBC13 in regulating paclitaxel sensitivity through a DNMT1-CHFR-Aurora A pathway in ovarian cancer cells. UBC13 could potentially be employed as a therapeutic molecular drug for reversing paclitaxel resistance in ovarian cancer patients.
Highlights
Ovarian cancer still presents the highest lethality of all gynecological tumors after decades of research, with an overall 5-year survival rate of 46%1
For the first time according to our knowledge, that paclitaxel-induced UBC13 down-regulation led to DNMT1 (DNA methyltransferase 1) degradation depression by decreased ubiquitination, which resulted in reduced expression of CHFR by promoter hypermethylation, and this induced Aurora A overexpression
We identified 60 proteins that were differentially expressed between SKOV3 and SKOV3-TR30 cells from 49 protein spots by the MALDI-TOF/TOF MS and MS/MS methods through International Protein Index (IPI) database, among which there were 38 downregulated and 22 up-regulated proteins with more than 1.5-fold quantitative alterations in the SKOV3-TR30 cells
Summary
Ovarian cancer still presents the highest lethality of all gynecological tumors after decades of research, with an overall 5-year survival rate of 46%1. Zhang et al Cell Death and Disease (2018)9:93 functions in regulating the sensitivity of tumor cells to chemotherapy agents[8,9,10], including paclitaxel[8]. Most of these studies focus on the relationship between chemotherapy and ubiquitin-ligases (E3), which are numerously encoded by the human genome[11]. Owing to the central role of ubiquitination in the life activity of cells, the discovery of UBC13 function and the signaling pathway involved during the paclitaxel resistance process would accelerate the progress of studies on reversing paclitaxel resistance in ovarian cancer
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