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Stat3 contributes to cancer progression by regulating Jab1/Csn5 expression.

ABSTRACT: Our previous studies demonstrated that Jab1/Csn5 overexpression is correlated with low survival rates in cancer patients, including nasopharyngeal carcinoma (NPC), breast cancer and hepatocellular carcinoma, and contributes to NPC's resistance to radiotherapy and cisplatin by regulating DNA damage and repair pathways. However, the molecular mechanism by which Jab1/Csn5 expression is upregulated in NPCs has yet to be determined. In the present study, we identified the upstream regulator of Jab1/Csn5 expression and demonstrated its role in intrinsic resistance of NPC cells to treatment with cisplatin. Signal transducer and activator of transcription-3 (Stat3) expression correlates with and contributes to Jab1/Csn5 transcription. Consistently, silencing of Stat3 in tumors reduced Jab1/Csn5 expression, thereby sensitizing NPC cells to cisplatin-induced apoptosis both in vitro and in vivo. Mechanistically, Stat3 transcriptionally regulated Jab1/Csn5. Furthermore, high mRNA expression levels of Stat3 or Jab1 in colon cancer, breast cancer and glioblastoma are associated with significantly shorter survival times from the R2 online database. These findings identify a novel Stat3-Jab1/Csn5 signaling axis in cancer pathogenesis with therapeutic and prognostic relevance.

SUBMITTER: Pan Y

PROVIDER: S-EPMC5311075 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Stat3 contributes to cancer progression by regulating Jab1/Csn5 expression.

Pan Y Y Wang S S Su B B Zhou F F Zhang R R Xu T T Zhang R R Leventaki V V Drakos E E Liu W W Claret F X FX

Oncogene 20160815 8

Our previous studies demonstrated that Jab1/Csn5 overexpression is correlated with low survival rates in cancer patients, including nasopharyngeal carcinoma (NPC), breast cancer and hepatocellular carcinoma, and contributes to NPC's resistance to radiotherapy and cisplatin by regulating DNA damage and repair pathways. However, the molecular mechanism by which Jab1/Csn5 expression is upregulated in NPCs has yet to be determined. In the present study, we identified the upstream regulator of Jab1/C ...[more]

PMID: 27524414

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Project description:IntroductionThe c-Jun coactivator, Jun activation-domain binding protein 1 (Jab1) also known as the fifth component of the COP9 signalosome complex (CSN5), is a novel candidate oncogene whose aberrant expression contributes to the progression of breast carcinoma and other human cancers. The mechanism of Jab1 gene expression and its deregulation in cancer cells remains to be identified. We therefore investigated the transcriptional regulatory mechanisms of Jab1 expression in human breast carcinoma cells.MethodsTo identify potential regulators of Jab1 transcription, we cloned the 5' upstream region of the human Jab1 gene and mapped its transcriptional start site. We identified binding sequences for the CCAAT/enhancer binding protein (C/EBP) and GATA, as well as a signal transducer and activator of transcription-3 (Stat3) consensus sequence overlapping the C/EBP site, using 5'- deletion analysis and a gene reporter assay. Mutational analysis of these binding sites was performed to confirm their roles in promoting Jab1 transcription in breast cancer cells. We further confirmed these binding sites using electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays. We also analyzed whether the siRNA-mediated inactivation of Stat3 and Src could reduce Jab1-promoter activity and whether interleukine-6 (IL-6) could mediate increased Jab1 expression through Stat3 signaling.ResultsWe identified binding sequences for C/EBP, GATA, as well as a Stat3 consensus sequence overlapping the C/EBP site in the promoter region of Jab1. C/EBP-beta2 is a potential transcriptional activator of Jab1 and mutation of the C/EBP/Stat3 binding site significantly reduced Jab1-promoter activity. In addition, inhibiting Stat3 significantly reduced Jab1-promoter activation. EMSA and ChIP assays confirmed that C/EBP, GATA1 and Stat3 bind to Jab1 promoter in breast carcinoma cells. We also found that Src, an activator of Stat3, is involved in Jab1-promoter activation. siRNA knockdown of Src reduced the Jab1-promoter activity, similar to the results seen when Stat3 was inhibited in breast carcinoma cells. Interestingly, reactivation of Stat3 in normal mammary epithelial cells (MCF-10A, MCF-10F) is sufficient to reactivate Jab1 expression. Treatment with the cytokine IL-6 resulted in increased Jab1 expression that was blocked by inhibition of Stat3.ConclusionsThese findings reveal a novel mechanism of Jab1 gene regulation and provide functional and mechanistic links between the Src/Stat3 and IL-6/Stat3 signaling axes that are involved in the activation of Jab1 transcription and regulation of this novel oncogenic protein.

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Stat3 contributes to cancer progression by regulating Jab1/Csn5 expression.

Publications

Stat3 contributes to cancer progression by regulating Jab1/Csn5 expression.

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