epz-6438 and 3-deazaneplanocin

Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

Topics: Adenosine; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Cell Cycle; Cell Transformation, Neoplastic; Clinical Trials as Topic; Combined Modality Therapy; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Epigenetic Repression; Histone Code; Histones; Humans; Methylation; Morpholines; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Polycomb Repressive Complex 2; Pyridones; Structure-Activity Relationship; Transcriptional Activation; Tumor Microenvironment

Trimethylation of lysine 27 and dimethylation of lysine 9 of histone-H3 catalyzed by the histone methyltransferases EZH2 and G9a impede gene transcription in cancer. Our human bronchial epithelial (HBEC) pre-malignancy model studied the role of these histone modifications in transformation. Tobacco carcinogen transformed HBEC lines were characterized for cytosine DNA methylation, transcriptome reprogramming, and the effect of inhibiting EZH2 and G9a on the transformed phenotype. The effects of targeting EZH2 and G9a on lung cancer prevention was assessed in the A/J mouse lung tumor model.. Carcinogen exposure induced transformation and DNA methylation of 12-96 genes in the four HBEC transformed (T) lines that was perpetuated in malignant tumors. In contrast, 506 unmethylated genes showed reduced expression in one or more HBECTs with many becoming methylated in tumors. ChIP-on-chip for HBEC2T identified 327 and 143 genes enriched for H3K27me3 and H3K9me2. Treatment of HBEC2T and HBEC13T with DZNep, a lysine methyltransferase inhibitor depleted EZH2, reversed transformation, and induced transcriptional reprogramming. The EZH2 small molecule inhibitor EPZ6438 also affected transformation and expression in HBEC2T, while a G9a inhibitor, UNC0642 was ineffective. Genetic knock down of EZH2 dramatically reduced carcinogen-induced transformation of HBEC2. Only DZNep treatment prevented progression of hyperplasia to adenomas in the NNK mouse lung tumor model through reducing EZH2 and affecting the expression of genes regulating cell growth and invasion.. These studies demonstrate a critical role for EZH2 catalyzed histone modifications for premalignancy and its potential as a target for chemoprevention of lung carcinogenesis.

Topics: Adenosine; Adenosylhomocysteinase; Animals; Benzamides; Biphenyl Compounds; Cell Proliferation; Chromatin Assembly and Disassembly; CpG Islands; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Epigenesis, Genetic; Epithelial Cells; Female; Histone Code; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Lung Neoplasms; Mice; Morpholines; Neoplasms; Phenotype; Pyridones; Transcriptome

Allogeneic hematopoietic cell transplantation is often complicated by graft versus host disease (GvHD), primarily mediated through allo-reactive donor T cells in the donor stem cell graft. Enhancer of Zeste Homolog 2 (EZH2), a histone-lysine N-methyltransferase and a component of the Polycomb Repressive Complex 2, has been shown to play a role in GvHD pathology. Although not yet clear, one proposed mechanism is through selective tri-methylation of lysine 27 in histone 3 (H3K27me3) that marks the promoter region of multiple pro-apoptotic genes, leading to repression of these genes in allo-reactive T cells. We found that selective pharmacologic inhibition of H3K27me3 with EPZ6438 or GSK126 did not prevent murine GvHD. This suggests the GvHD mitigating properties of DZNep are independent from H3K27me3 inhibition. Furthermore, while pharmacologic inhibition of EZH2 by DZNep has been shown to be effective in abrogating mouse GvHD, we found that DZNep was not effective in preventing GvHD in a human T cell xenograft mouse model. Although EZH2 is an attractive target to harness donor allo-reactive T cells in the post-transplant setting to modulate GvHD and the anti-leukemia effect, our results suggest that more selective and effective ways to inhibit EZH2 in human T cells are required.

Topics: Adenosine; Animals; Benzamides; Biphenyl Compounds; Cells, Cultured; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histone Code; Histones; Humans; Indoles; Methylation; Mice; Morpholines; Pyridones; T-Lymphocytes