title: A polymorphism in JMJD2C alters the cleavage by caspase-3 and the prognosis of human breast cancer.
abstract: JMJD2C is a candidate oncogene that encodes a histone lysine demethylase with the ability to demethylate the lysine 9 residue of histone H3 (H3K9). The expression levels of JMJD2C are associated with tumor development and clinical outcome. Here we identify JMJD2C as a new substrate for caspase-3. JMJD2C is cleaved by caspase-3 at DEVD396G motif and then loses its demethylase activity. Additionally, we uncover D396N polymorphism (rs2296067) in the cleavage site of JMJD2C and establish its influence on the resistant to the cleavage by caspase-3. Importantly, we determined that D396N polymorphism is significantly associated with the prognosis of human breast cancer. We further found that the basal levels of DSB (double strand DNA break) repair proteins γ-H2AX (gamma-H2AX) increased when cells were treated with tumor necrosis factor-α (TNF-α) which activates caspase-3 activity. We also show that knockdown of JMJD2C expression results in up-regulation of basal γ-H2AX. We propose that D396N polymorphism of JMJD2C affects the prognosis of human breast cancer via altering the cleavage by caspase-3 and the ability of DSB repair which may contribute to therapy resistance.
authors: Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors: Qi
authors: Q
authors: Hong
authors: Sanjian
authors: S
authors: Yu
authors: Yu
authors: Y
authors: Yang
authors: Guangyu
authors: G
authors: Liu
authors: Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors: Zhiming
authors: Z
authors: Shao
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics; D020536:Enzyme Activators / Q000494:pharmacology; D005787:Gene Frequency; D005838:Genotype; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D034622:RNA Interference; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020536:Enzyme Activators; C468783:H2AX protein, human; D006657:Histones; C413655:KDM4C protein, human; D014409:Tumor Necrosis Factor-alpha; D056484:Jumonji Domain-Containing Histone Demethylases; D053148:Caspase 3