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Research Papers:

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

Benoît Romain, Radhia Benbrika-Nehmar, Laetitia Marisa, Michèle Legrain, Viviane Lobstein, Attila Oravecz, Laetitia Poidevin, Cyril Bour, Jean-Noël Freund, Isabelle Duluc, Dominique Guenot _ and Erwan Pencreach

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Oncotarget. 2017; 8:38351-38366. https://doi.org/10.18632/oncotarget.16323

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Abstract

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

Correspondence to:

Dominique Guenot, email: dominique.guenot@inserm.u-strasbg.fr

Keywords: chemokine, valproate, butyrate, PCAF, acetylation

Received: March 17, 2016     Accepted: February 27, 2017     Published: March 17, 2017

ABSTRACT

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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