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Jumonji domain-containing protein 2B silencing induces DNA damage response via STAT3 pathway in colorectal cancer.

ABSTRACT: BACKGROUND: Jumonji domain-containing protein 2B (JMJD2B), directly targeted by hypoxia-inducible factor 1?, maintains the histone methylation balance important for the transcriptional activation of many oncogenes. Jumonji domain-containing protein 2B has been implicated in colorectal cancer (CRC) progression; however, the mechanism remains unclear. METHODS: Immunofluorescence and western blotting detected phosphorylated histone H2AX, characteristic of double-strand breaks, and comet assay was used to investigate DNA damage, in CRC cells after JMJD2B small interfering RNA (siRNA) transfection. We assessed the resulting in vitro responses, that is, cell cycle progression, apoptosis, and senescence coupled with JMJD2B silencing-induced DNA damage, studying the regulatory role of signal transducers and activators of transcription 3 (STAT3). The JMJD2B silencing anti-cancer effect was determined using an in vivo CRC xenograft model. RESULTS: Jumonji domain-containing protein 2B knockdown induced DNA damage via ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related pathway activation, resulting in cell cycle arrest, apoptosis, and senescence in both normoxia and hypoxia. Signal transducers and activators of transcription 3 suppression by JMJD2B silencing enhanced DNA damage. Intratumoural injection of JMJD2B siRNA suppressed tumour growth in vivo and activated the DNA damage response (DDR). CONCLUSIONS: Jumonji domain-containing protein 2B has an essential role in cancer cell survival and tumour growth via DDR mediation, which STAT3 partially regulates, suggesting that JMJD2B is a potential anti-cancer target.

SUBMITTER: Chen L

PROVIDER: S-EPMC3929886 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other

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Jumonji domain-containing protein 2B silencing induces DNA damage response via STAT3 pathway in colorectal cancer.

Chen L L Fu L L Kong X X Xu J J Wang Z Z Ma X X Akiyama Y Y Chen Y Y Fang J J

British journal of cancer 20140128 4

<h4>Background</h4>Jumonji domain-containing protein 2B (JMJD2B), directly targeted by hypoxia-inducible factor 1α, maintains the histone methylation balance important for the transcriptional activation of many oncogenes. Jumonji domain-containing protein 2B has been implicated in colorectal cancer (CRC) progression; however, the mechanism remains unclear.<h4>Methods</h4>Immunofluorescence and western blotting detected phosphorylated histone H2AX, characteristic of double-strand breaks, and come ...[more]

PMID: 24473398

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Project description:Background and purposeWhite matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.MethodsChronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.ResultsDisruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling.ConclusionsOur study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.

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Jumonji domain-containing protein 2B silencing induces DNA damage response via STAT3 pathway in colorectal cancer.

Publications

Jumonji domain-containing protein 2B silencing induces DNA damage response via STAT3 pathway in colorectal cancer.

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