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Upstream transcription factor 1 prompts malignancies of cervical cancer primarily by transcriptionally activating p65 expression.

ABSTRACT: Cervical cancer is the third-most common cause of female cancer-related mortality worldwide. In cervical cancer, aberrant activation of nuclear factor (NF)-?B signaling is widely reported. However, the transcriptional regulation of NF-?B signaling remains unclear. The present study aimed to explore the underlying mechanism in which NF-?B signaling was activated in cervical cancer cells. Initially, the expression of p65 was demonstrated to be markedly enhanced in grade II, III or IV cervical cancer tissues compared with that of normal cervical tissues, indicating that p65 expression was correlated with tumor grade. In HeLa and CaSki cells, overexpression of p65 markedly enhanced cervical cancer cell invasion and migration. Further experiments demonstrated that p65 overexpression significantly increased the phosphorylation levels of protein kinase B (AKT) and p38. Dual luciferase reporter and chromatin immunoprecipitation assays demonstrated that USF1 was able to bind the promoter region of p65, thereby enhancing the transcriptional activation of p65. Notably, when p65 was silenced, the phosphorylation levels of AKT and p38 were suppressed even in cells transfected with adenovirus vectors expressing upstream transcription factor 1 (USF1). These data indicated that USF1 prompted cervical cancer progression primarily by transcriptionally activating p65. In conclusion, the present study demonstrated that USF1 was able to activate the transcription of p65, thereby enhancing the malignancy of cervical cancer cells.

SUBMITTER: Wang W

PROVIDER: S-EPMC6257725 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Upstream transcription factor 1 prompts malignancies of cervical cancer primarily by transcriptionally activating p65 expression.

Wang Wen W Yao Shujuan S Jiang Hongjing H Dong Jing J Cui Xiujuan X Tian Xiangyu X Guo Yanyan Y Zhang Shiqian S

Experimental and therapeutic medicine 20180918 6

Cervical cancer is the third-most common cause of female cancer-related mortality worldwide. In cervical cancer, aberrant activation of nuclear factor (NF)-κB signaling is widely reported. However, the transcriptional regulation of NF-κB signaling remains unclear. The present study aimed to explore the underlying mechanism in which NF-κB signaling was activated in cervical cancer cells. Initially, the expression of p65 was demonstrated to be markedly enhanced in grade II, III or IV cervical canc ...[more]

PMID: 30542391

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Project description:Taxol (paclitaxel) is a potent anticancer drug that has been found to be effective against several tumor types, including cervical cancer. However, the exact mechanism underlying the antitumor effects of paclitaxel is poorly understood. Here, paclitaxel induced the apoptosis of cervical cancer HeLa cells and correlated with the enhanced activation of caspase-3 and TAp73, which was strongly inhibited by TAp73beta small interfering RNA (siRNA). In wild-type activating transcription factor 3 (ATF3)-overexpressed cells, paclitaxel enhanced apoptosis through increased alpha and beta isoform expression of TAp73; however, these events were attenuated in cells containing inactive COOH-terminal-deleted ATF3 [ATF3(DeltaC)] or ATF3 siRNA. In contrast, paclitaxel-induced ATF3 expression did not change in TAp73beta-overexpressed or TAp73beta siRNA-cotransfected cells. Furthermore, paclitaxel-induced ATF3 translocated into the nucleus where TAp73beta is expressed, but not in ATF3(DeltaC) or TAp73beta siRNA-transfected cells. As confirmed by the GST pull-down assay, ATF3 bound to the DNA-binding domain of p73, resulting in the activation of p21 or Bax transcription, a downstream target of p73. Overexpression of ATF3 prolonged the half-life of TAp73beta by inhibiting its ubiquitination and thereby enhancing its transactivation and proapoptotic activities. Additionally, ATF3 induced by paclitaxel potentiated the stability of TAp73beta, not its transcriptional level. Chromatin immunoprecipitation analyses show that TAp73beta and ATF3 are recruited directly to the p21 and Bax promoter. Collectively, these results reveal that overexpression of ATF3 potentiates paclitaxel-induced apoptosis of HeLa cells, at least in part, by enhancing TAp73beta's stability and its transcriptional activity. The investigation shows that ATF3 may function as a tumor-inhibiting factor through direct regulatory effects on TAp73beta, suggesting a functional link between ATF3 and TAp73beta.

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Upstream transcription factor 1 prompts malignancies of cervical cancer primarily by transcriptionally activating p65 expression.

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Upstream transcription factor 1 prompts malignancies of cervical cancer primarily by transcriptionally activating p65 expression.

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