gsk-2816126 and Carcinogenesis

Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, because of the low efficacy of current therapeutic strategies. Estrogen-related receptor γ (ERRγ) was previously showed as a suppressor of GC. However, the mechanism and effective therapeutic method based on ERRγ is yet to be developed.. The expression levels of ERRγ, EZH2, and FOXM1 were detected by immunohistochemistry, qRT-PCR, and western blot. The regulatory mechanisms of ERRγ and FOXM1 were analyzed by ChIP, EMSA, and siRNA. The effects of EZH2 inhibitor (GSK126) or/and ERRγ agonist (DY131) on the tumorigenesis of gastric cancer cell lines were examined by cell proliferation, transwell migration, wound healing, and colony formation assays. Meanwhile, the inhibitory effects of GSK126 or/and DY131 on tumor growth were analyzed by xenograft tumor growth assay.. The expression of ERRγ was suppressed in tumor tissues of GC patients and positively correlated with prognosis, as opposed to that of EZH2 and FOXM1. EZH2 transcriptionally suppressed ERRγ via H3K27me3, which subsequently activated the expression of master oncogene FOXM1. The combination of GSK126 and DY131 synergistically activated ERRγ expression, which subsequently inhibited the expression of FOXM1 and its regulated pathways. Synergistic combination of GSK126 and DY131 significantly inhibited the tumorigenesis of GC cell lines and suppressed the growth of GC xenograft.. The FOXM1 signaling pathway underlying the ERRγ-mediated gastric cancer suppression was identified. Furthermore, combined treatment with EZH2 inhibitor and ERRγ agonist synergistically suppressed GC progression by inhibiting this signaling pathway, suggesting its high potential in treating GC patients.

Topics: Carcinogenesis; Cell Line, Tumor; Drug Therapy, Combination; Enhancer of Zeste Homolog 2 Protein; Forkhead Box Protein M1; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Indoles; Pyridones; Receptors, Estrogen; Signal Transduction; Stomach Neoplasms; Xenograft Model Antitumor Assays

Highly invasive and rapidly fatal, small-cell lung cancer (SCLC) has been an insurmountable gulf since discovery. Innate immunity plays a vital role in anti-tumor response, among which macrophages contribute to an indispensable character. Here, we found that macrophage infiltration in SCLC reduced significantly in a stage-dependent manner, attributed to the decreased expression of CCL2, a potent chemoattractant for monocytes. Validated by ChIP-qPCR and MassArray methylation analysis, CCL2 expression was inhibited by EZH2-mediated H3K27me3 in the enhancer regions and DNMT1-mediated DNA methylation in the promoter regions, the process of which could be reversed by small-molecular compounds, EPZ011989 and Decitabine. Direct cell-cell contact between SCLC cells and macrophages skewed the phenotype of macrophages to be more M1-like. Furthermore, in an ectopic engraft model of SCLC, disruption of EZH2/DNMT1 function using the combination treatment of EPZ011989 and Decitabine potently abrogated the inhibition of macrophage infiltration and thus suppressed tumor growth, the effect of which was impaired by CCL2 neutralization or macrophage depletion. Overall, this work provides new insights into the role of macrophages in SCLC and establishes a rationale for constructing novel therapeutic avenues for SCLC patients.

Topics: Adolescent; Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Chemokine CCL2; CpG Islands; Decitabine; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Enhancer Elements, Genetic; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Female; Histones; Humans; Indoles; Lung; Lung Neoplasms; Male; Mice; Middle Aged; Phagocytosis; Pyridones; Small Cell Lung Carcinoma; Tissue Array Analysis; Tumor-Associated Macrophages; Xenograft Model Antitumor Assays; Young Adult

The histone methyltransferase EZH2, a key epigenetic modifier, is known to be associated with human tumorigenesis. However, the physiological importance of EZH2 and its clinical relevance in endometrial cancer remain unclear. Hence, in the present study, we investigated the expression and function of EZH2 in endometrial cancer. In a quantitative real-time PCR analysis of 11 endometrial cancer cell lines and 52 clinical endometrial cancer specimens, EZH2 was significantly overexpressed in cancer cells and tissues compared to that in corresponding normal control cells and tissues. Kaplan-Meier survival analysis using data of the TCGA RNA-seq database and tissue microarrays (TMAs) indicated that EZH2 overexpression is associated with endometrial cancer prognosis. In addition, knockdown of EZH2 using specific siRNAs resulted in growth suppression and apoptosis induction of endometrial cancer cells, accompanied by attenuation of H3K27 trimethylation. Consistent with these results, treatment with GSK126, a specific EZH2 inhibitor, suppressed endometrial cancer cell growth and decreased the number of cancer cell colonies. Furthermore, GSK126 showed additive effects with doxorubicin or cisplatin, which are conventional drugs for treatment of endometrial cancer. Further studies should explore the therapeutic potential of inhibiting EZH2 in patients with endometrial cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Doxorubicin; Endometrial Neoplasms; Enhancer of Zeste Homolog 2 Protein; Female; Genetic Markers; Histones; Humans; Indoles; Prognosis; Pyridones; RNA Interference; RNA, Small Interfering