RESUMO
Dysregulated expression of histone methyltransferases and demethylases is an emerging epigenetic mechanism underlying cancer development and metastasis. We recently showed that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is necessary for tumorigenic and metastatic capabilities of KDM2A-overexpressing non-small cell lung cancer (NSCLC) cells. Here, we report that KDM2A transcriptionally represses the histone deacetylase 3 (HDAC3) gene by removing methyl groups from dimethylated H3K36 at the HDAC3 promoter in KDM2A-overexpressing NSCLC cells. KDM2A depletion reduced expression levels of cell cycle-associated genes (e.g. CDK6) and cell invasion-related genes (e.g. NANOS1); these levels were rescued by ectopic expression of KDM2A but not its catalytic mutant. These genes were occupied and down-regulated by HDAC3. HDAC3 knockdown significantly recovered the proliferation and invasiveness of KDM2A-depleted NSCLC cells as well as the levels of CDK6 and NANOS1 expression in these cells. Similar to their previously reported functions in other cell types, CDK6 and NANOS1 were required for the proliferation and invasion, respectively, of KDM2A-overexpressing NSCLC cells. In a mouse xenograft model, HDAC3 depletion substantially restored the tumorigenic ability of KDM2A knockdown cells. These findings reveal a novel cancer-epigenetic pathway in which the antagonistic effect of KDM2A on HDAC3 expression releases cell cycle-associated genes and cell invasion-related genes from HDAC3 repression and indicate the importance of this pathway for tumorigenicity and invasiveness of KDM2A-overexpressing NSCLC cells.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Epigênese Genética , Proteínas F-Box/metabolismo , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Pulmonares/metabolismo , Transcrição Gênica , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Quinase 6 Dependente de Ciclina/metabolismo , Proteínas F-Box/genética , Técnicas de Silenciamento de Genes , Inativação Gênica , Histona Desacetilases/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/metabolismoRESUMO
Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A1*6 and UGT1A9*22 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A1*28 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A1*6, UGT1A7*3, and UGT1A9*22 polymorphisms than in controls. The presence of the UGT1A1*6 allele also showed a significant association with grade III-IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A1*6 or UGT1A7*3 variant also had the UGT1A9*22 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A9*22 polymorphism. By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of severe toxicity such as intense diarrhea or neutropenia.
RESUMO
Epigenetic dysregulation has emerged as a major contributor to tumorigenesis. Histone methylation is a well-established mechanism of epigenetic regulation that is dynamically modulated by histone methyltransferases and demethylases. The pathogenic role of histone methylation modifiers in non-small cell lung cancer (NSCLC), which is the leading cause of cancer deaths worldwide, remains largely unknown. Here, we found that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is frequently overexpressed in NSCLC tumors and cell lines. KDM2A and its catalytic activity were required for in vitro proliferation and invasion of KDM2A-overexpressing NSCLC cells. KDM2A overexpression in NSCLC cells with low KDM2A levels increased cell proliferation and invasiveness. KDM2A knockdown abrogated tumor growth and invasive abilities of NSCLC cells in mouse xenograft models. We identified dual-specificity phosphatase 3 (DUSP3) as a key KDM2A target gene and found that DUSP3 dephosphorylates ERK1/2 in NSCLC cells. KDM2A activated ERK1/2 through epigenetic repression of DUSP3 expression via demethylation of dimethylated H3K36 at the DUSP3 locus. High KDM2A levels correlated with poor prognosis in NSCLC patients. These findings uncover an unexpected role for a histone methylation modifier in activating ERK1/2 in lung tumorigenesis and metastasis, suggesting that KDM2A may be a promising therapeutic target in NSCLC.