gsk-2816126 and Small-Cell-Lung-Carcinoma

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

Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. Expression array analysis of 23 SCLC cases and 42 normal tissues revealed that EZH2 and other PRC2 members were highly expressed in SCLC. ChIP-seq for H3K27me3 suggested that genes with H3K27me3(+) in SCLC were extended not only to PRC2-target genes in ES cells but also to other target genes such as cellular adhesion-related genes. These H3K27me3(+) genes in SCLC were repressed significantly, and introduction of the most repressed gene JUB into SCLC cell line lead to growth inhibition. Shorter overall survival of clinical SCLC cases correlated to repression of JUB alone, or a set of four genes including H3K27me3(+) genes. Treatment with EZH2 inhibitors, DZNep and GSK126, resulted in growth repression of SCLC cell lines. High PRC2 expression was suggested to contribute to gene repression in SCLC, and may play a role in genesis of SCLC.

Topics: Biomarkers, Tumor; Blotting, Western; Case-Control Studies; Cell Proliferation; Chromatin Immunoprecipitation; Enhancer of Zeste Homolog 2 Protein; Fluorescent Antibody Technique; Gene Expression Profiling; Histones; Humans; Indoles; Jumonji Domain-Containing Histone Demethylases; LIM Domain Proteins; Lung; Lung Neoplasms; Oligonucleotide Array Sequence Analysis; Polycomb Repressive Complex 2; Prognosis; Pyridones; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Small Cell Lung Carcinoma; Survival Rate; Tumor Cells, Cultured