A polymorphism in JMJD2C alters the cleavage by caspase-3 and the prognosis of human breast cancer
نویسندگان
چکیده
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.
منابع مشابه
Induction of Apoptosis in Human Breast Cancer MCF-7 Cells by a Semi-Synthetic Derivative of Artemisinin: A Caspase-Related Mechanism
Background: Artesunate has recently been used in some pharmacological preparation to induce tumor cell apoptosis. The drug is a semi-synthetic derivative of artemisinin, traditionally used for its antimalarial. However, up to now, its anticancer mechanism against diff erent types of tumors is not known.Objectives: The most important purposes of the present research was fi...
متن کاملAnti-proliferative effect and apoptotic induction of sesquiterpene lactone parthenolide in a human breast cancer cell line
Parthenolide is a secondary metabolite, which naturally occurs in the feverfew plant and is responsible for its healing power. The potential of parthenolide in inhibition of cancer cell growth, alone or in combination with other anti-cancer therapeutics, have been studied in several laboratories. In this study, the effect of extracted parthenolide on the expression of seven pro-apoptotic genes,...
متن کاملCASPASE DEPENDENT APOPTOSIS INDUCED BY CLADRIBINE IN THE ESTROGEN RECEPTOR NEGATIVE BREAST CANCER CELL LINE, MDA-MB468
The purpose of the present study is to investigate the cytotoxicity/apoptotic effect of 2-chloro-2′-deoxyadenosine, cladribine, (2-CdA) in the human breast cancer cell line, MDA-MB468 (estrogen receptor negative, ER−). MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] assay, annexin V-Fluorescein/PI and Hoechst 33258 staining were used to detect cytotoxicity and cell apopto...
متن کاملGenetic Polymorphism of the Glutathione S-Transferase M1 and Development of Breast Cancer
Glutathione S-transferases (GSTs) are encoded by a superfamily of genes and play a role in the detoxification of potential carcinogens. The human GSTs are divided into four classes: alpha, mu, pi and theta. Previous studies indicated that the absence of the Glutathione S-Transferase M1 (GSTM1) protein correlated with an increased risk of developing some types of cancers. Association between spe...
متن کاملCytotoxicity Effect of Cladribine on the MCF-7 Human Breast Cancer Cell Line
Cladribine, an analogue of deoxyadenosine, is highly toxic for both non-dividing and proliferating cells and has shown activity in the treatment of several malignancies. Therefore, the aim of the present study is to investigate the cytotoxicity effect of cladribine (2-CdA) on the breast cancer cell line, MCF-7 (estrogen receptor positive, ER+). MTT assay, annexin V-Fluorescein/PI and Hoechst 33...
متن کامل