Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration
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Benoît Romain1,2, Radhia Benbrika-Nehmar1, Laetitia Marisa3, Michèle Legrain4, Viviane Lobstein1, Attila Oravecz5, Laetitia Poidevin5, Cyril Bour1, Jean-Noël Freund6, Isabelle Duluc6, Dominique Guenot1, Erwan Pencreach1,4,7
1Université de Strasbourg, Progression Tumorale et Microenvironnement, Approches Translationnelles et Epidémiologie, Strasbourg, France
2Hôpitaux Universitaires de Strasbourg, Service de Chirurgie Générale et Digestive, Strasbourg, France
3Cartes d’Identité des Tumeurs Program, Ligue Nationale Contre le Cancer, Paris, France
4Hôpitaux Universitaires de Strasbourg, Laboratoire de Biochimie et Biologie Moléculaire, Strasbourg, France
5Université de Strasbourg, CNRS, Department of Computer Science, ICube, Strasbourg, France
6Université de Strasbourg, INSERM Unit 1113, Strasbourg, France
7Hôpitaux Universitaires de Strasbourg, Centre de Ressources Biologiques, Département de Pathologie, Strasbourg, France
Dominique Guenot, email: [email protected]
Keywords: chemokine, valproate, butyrate, PCAF, acetylation
Received: March 17, 2016 Accepted: February 27, 2017 Published: March 17, 2017
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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