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

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.

MicroRNA-29a represses osteoclast formation and protects against osteoporosis by regulating PCAF-mediated RANKL and CXCL12

“…On the other hand, the acetylation state of histone assembly regulated by histone acetyltransferase and deacetylase is known to alter CXCL12 transcription in osteoblasts and synovial fibroblasts 36–38 . PCAF signaling is found to regulate the acetylation status of CXCL12 promoter 39 and osteogenic differentiation of mesenchymal stem cell cultures 40 . Our study further uncovered a noncanonical pathway that miR-29a inhibition of PCAF interfered with CXCL12 expression through H3K27 hypoacetylation and thus downregulated the H3K27ac occupancy in CXCL12 promoter in osteoblast cultures.…”

Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases

“…Class I HDAC inhibition using apicidin decreased its expression in pulmonary fibroblasts, demonstrating that class I HDACs induces CXCL12 expression [ 66 ]. However, in colon cancer cells, Romain et al observed that non-specific HDAC inhibition by vorinostat, valproic acid, butyrate increased CXCL12 expression, which was otherwise decreased in both MSI and MSS colon cancer tumors, warranting more studies on the roles of specific HDACs on CXCL12 expression [ 106 ].…”

VprBP directs epigenetic gene silencing through histone H2A phosphorylation in colon cancer

“…Colon cancer is a leading cause of cancer deaths in the world and has been considered to arise from genetic alterations in genes encoding factors that help control cell growth and proliferation [ 12 , 13 ]. However, accumulating evidence indicates that epigenetic alterations generated by dysregulation of epigenetic modifiers play pivotal roles in the initiation, promotion, and progression of colon cancer [ 14 , 15 , 16 , 17 ]. Especially, histone modification is increasingly recognized as an essential process to control oncogenic transcription program and influence the occurrence and development of colon cancer [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”