The p300/CBP - associated factor is frequently down-regulated in intestinal-type gastric carcinoma and constitutes a biomarker for clinical outcome

Mao, Ying; Wang, Jiejun; Li, Dawei; Yu, Guan; Wang, Xi; Pan, Jun; Chen, Ying; He, Miaoxia

doi:10.4161/cbt.9.4.10748

Cited by 44 publications

(25 citation statements)

References 29 publications

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“…We also demonstrated that loss of PCAF expression is an early event in colon cancer initiation, observed at the adenoma stage and maintained in carcinomas that correlates with CXCL12 silencing in human tumors. Loss of PCAF has already been described in pancreatic cancer, endometrial tumors or head and neck carcinomas, and has been implicated in different molecular processes regulating tumor initiation and/or progression [23–25]. Here we also show that forced-expression of PCAF in SW480 non-CXCL12 expressing cells, is a powerful inducer of CXCXL12, providing further evidence that in addition to methylation, level of promoter acetylation may participate to regulate CXCL12 expression in colon cancer cells.…”

Section: Discussionsupporting

confidence: 81%

Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration

et al. 2017

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CXCL12 has been shown to be involved in colon cancer metastasis, but its expression level and molecular mechanisms regulating its expression remain controversial. We thus evaluated CXCL12 expression in a large cohort of colon adenomas and carcinomas, investigated for an epigenetic mechanism controlling its expression and evaluated the impact of CXCL12 levels on cell migration and tumor growth. CXCL12 expression was measured in human colon adenomas and carcinomas with transcriptome array and RT-qPCR. The promoter methylation was analyzed with whole-genome DNA methylation chips and protein expression by immunohistochemistry. We confirm a reduced expression of CXCL12 in 75% of MSS carcinomas and show that the decrease is an early event as already present in adenomas. The methylome analysis shows that the CXCL12 promoter is methylated in only 30% of microsatellite-stable tumors. In vitro, treatments with HDAC inhibitors, butyrate and valproate restored CXCL12 expression in three colon cell lines, increased acetylation of histone H3 within the CXCL12 promoter and inhibited cell migration. In vivo, valproate diminished (65%) the number of intestinal tumors in APC mutant mice, slowed down xenograft tumor growth concomitant to restored CXCL12 expression. Finally we identified loss of PCAF expression in tumor samples and showed that forced expression of PCAF in colon cancer cell lines restored CXCL12 expression. Thus, reduced PCAF expression may participate to CXCL12 promoter hypoacetylation and its subsequent loss of expression. Our study is of potential clinical interest because agents that promote or maintain histone acetylation through HDAC inhibition and/or HAT stimulation, may help to lower colon adenoma/carcinoma incidence, especially in high-risk families, or could be included in therapeutic protocols to treat advanced colon cancer.

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Section: Discussionsupporting

confidence: 81%

Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration

et al. 2017

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“…Inhibitors of SRC kinase activity have been used to treat gastric cancer (Nam et al, 2013). KAT2B is a histone lysine acetyltransferase that regulates gene transcription via interaction with p300/CREB-binding protein (Zhu et al, 2009); down-regulation of KAT2B promotes intestinal-type gastric cancer progression and is correlated with a poor clinical outcome (Ying et al, 2010). NR3C1 encodes glucocorticoid receptor which is associated with several biological process including inflammation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Combining multi-dimensional data to identify key genes and pathways in gastric cancer

Ren

Wang

et al. 2017

PeerJ

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Gastric cancer is an aggressive cancer that is often diagnosed late. Early detection and treatment require a better understanding of the molecular pathology of the disease. The present study combined data on gene expression and regulatory levels (microRNA, methylation, copy number) with the aim of identifying key genes and pathways for gastric cancer. Data used in this study was retrieved from The Cancer Genomic Atlas. Differential analyses between gastric cancer and normal tissues were carried out using Limma. Copy number alterations were identified for tumor samples. Bimodal filtering of differentially expressed genes (DEGs) based on regulatory changes was performed to identify candidate genes. Protein–protein interaction networks for candidate genes were generated by Cytoscape software. Gene ontology and pathway analyses were performed, and disease-associated network was constructed using the Agilent literature search plugin on Cytoscape. In total, we identified 3602 DEGs, 251 differentially expressed microRNAs, 604 differential methylation-sites, and 52 copy number altered regions. Three groups of candidate genes controlled by different regulatory mechanisms were screened out. Interaction networks for candidate genes were constructed consisting of 415, 228, and 233 genes, respectively, all of which were enriched in cell cycle, P53 signaling, DNA replication, viral carcinogenesis, HTLV-1 infection, and progesterone mediated oocyte maturation pathways. Nine hub genes (SRC, KAT2B, NR3C1, CDK6, MCM2, PRKDC, BLM, CCNE1, PARK2) were identified that were presumed to be key regulators of the networks; seven of these were shown to be implicated in gastric cancer through disease-associated network construction. The genes and pathways identified in our study may play pivotal roles in gastric carcinogenesis and have clinical significance.

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“…Accordingly, PCAF has been found to be down-regulated in HCC tissues compared with the adjacent non-tumor tissues and significantly associated with malignant portal vein invasion and poor survival of HCC patients [32]. PCAF expression has also been reported to be downregulated in HCC, gastric cancer and ovarian cancer [33]. In esophageal SCC, loss of PCAF locus correlated with advanced tumor stage and metastasis.…”

Section: Lysine Acetyltransferases Families and Their Link To Cancermentioning

confidence: 99%

The multifaceted role of lysine acetylation in cancer: prognostic biomarker and therapeutic target

Martile¹,

Bufalo²,

Trisciuoglio³

2016

Oncotarget

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Lysine acetylation is a post-translational modification that regulates gene transcription by targeting histones as well as a variety of transcription factors in the nucleus. Recently, several reports have demonstrated that numerous cytosolic proteins are also acetylated and that this modification, affecting protein activity, localization and stability has profound consequences on their cellular functions. Interestingly, most non-histone proteins targeted by acetylation are relevant for tumorigenesis. In this review, we will analyze the functional implications of lysine acetylation in different cellular compartments, and will examine our current understanding of lysine acetyltransferases family, highlighting the biological role and prognostic value of these enzymes and their substrates in cancer. The latter part of the article will address challenges and current status of molecules targeting lysine acetyltransferase enzymes in cancer therapy.

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The p300/CBP - associated factor is frequently down-regulated in intestinal-type gastric carcinoma and constitutes a biomarker for clinical outcome

Abstract: Reduced expression of PCAF plays an important role in the development of ITGC and correlates with a poor clinical outcome.

Cited by 44 publications

References 29 publications

Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration

Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration

Combining multi-dimensional data to identify key genes and pathways in gastric cancer

The multifaceted role of lysine acetylation in cancer: prognostic biomarker and therapeutic target

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