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 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.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.

SOCS1 Gene Therapy Improves Radiosensitivity and Enhances Irradiation-Induced DNA Damage in Esophageal Squamous Cell Carcinoma

“…Several reports have shown that STAT3 modulates the DNA damage response pathway (32,38,39). Accordingly, inhibition of activated STAT3 decreases DNA repair activity after IR (40,41). In this study, we demonstrated that the expression of gH2AX, which is an indicator of double-strand DNA breaks after IR, is enhanced in vitro and in vivo after combining radiotherapy with SOCS1 gene therapy, as compared with that with each monotherapy.…”

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

“…The epidermal growth factor receptor/STAT3 pathway upregulates the endonuclease, Eme1, to reduce DNA damage after topoisomerase I inhibition (Vigneron et al, 2008). JMJD2B, a hypoxia-inducible factor 1aregulated master regulator of DNA repair genes, which maintains histone methylation balance important for the transcriptional activation of many oncogenes, acts through activating STAT3 (Chen et al, 2014).…”

The association of changes in RAD51 and survivin expression levels with the proton beam sensitivity of Capan‑1 and Panc‑1 human pancreatic cancer cells

“…The current study determined that an increase in H2A.X phosphorylation and a decrease of STAT3 phosphorylation occurred simultaneously when the cells were irradiated with a PB. Chen et al (50) revealed that the inhibition of phosphorylated STAT3 was linked with an increase of H2A.X phosphorylation, indicating DNA damage. Furthermore, Wen et al revealed that apoptosis was enhanced with the phosphorylation of H2A.X by mammalian STE20-like kinase 1 (51).…”