Abstract
Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells.
Highlights
Cervical cancer is the second most common cancer among women under 65 years of age and the most frequent cause of death from gynecological cancers worldwide
We identified Ubiquitin B (UbB), which can covalently link to certain target proteins marking them for degradation by the ubiquitinproteasome system (UPS), as a mediator of cancer cell apoptosis induced by Trichostatin A (TSA)
Prolonged histone deacetylase inhibitor (HDACi)-selected HeLa/TSA cells were resistant to chemotherapy
Summary
Cervical cancer is the second most common cancer among women under 65 years of age and the most frequent cause of death from gynecological cancers worldwide. A woman's risk of developing cervical cancer by 65 years of age ranges from 0.69% in developed countries to 1.38% in developing countries. In 2010, approximately 75, 000 new cases of cervical cancer were diagnosed in China [1,2]. Approximately 35% of women diagnosed with cervical cancer have recurrent disease, with 90% of these found within 3 years after initial treatment [3]. Because of multi-drug resistance and resistance to radiotherapy, conventional methods will not be effective for recurrent cases. Improved targeted therapies and chemo/radio-sensitization strategies are essential for reducing the mortality of this devastating malignancy
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