Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration.
Résumé
CXCL12 has been shown to be involved in colon cancer metastasis, but itsexpression level and molecular mechanisms regulating its expression remaincontroversial. We thus evaluated CXCL12 expression in a large cohort of colon adenomasand carcinomas, investigated for an epigenetic mechanism controlling its expressionand evaluated the impact of CXCL12 levels on cell migration and tumor growth.CXCL12 expression was measured in human colon adenomas and carcinomas withtranscriptome array and RT-qPCR. The promoter methylation was analyzed with wholegenomeDNA methylation chips and protein expression by immunohistochemistry. Weconfirm a reduced expression of CXCL12 in 75% of MSS carcinomas and show that thedecrease is an early event as already present in adenomas. The methylome analysisshows that the CXCL12 promoter is methylated in only 30% of microsatellite-stabletumors. In vitro, treatments with HDAC inhibitors, butyrate and valproate restoredCXCL12 expression in three colon cell lines, increased acetylation of histone H3 withinthe CXCL12 promoter and inhibited cell migration. In vivo, valproate diminished (65%)the number of intestinal tumors in APC mutant mice, slowed down xenograft tumorgrowth concomitant to restored CXCL12 expression. Finally we identified loss of PCAFexpression in tumor samples and showed that forced expression of PCAF in coloncancer cell lines restored CXCL12 expression. Thus, reduced PCAF expression mayparticipate to CXCL12 promoter hypoacetylation and its subsequent loss of expression.Our study is of potential clinical interest because agents that promote or maintainhistone acetylation through HDAC inhibition and/or HAT stimulation, may help tolower colon adenoma/carcinoma incidence, especially in high-risk families, or couldbe included in therapeutic protocols to treat advanced colon cancer.
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