DNA methylation and histone modifications regulate SOX11 expression in lymphoid and solid cancer cells

Abstract

BackgroundThe neural transcription factor SOX11 is present at specific stages during embryo development with a very restricted expression in adult tissue, indicating precise regulation of transcription. SOX11 is strongly up-regulated in some malignancies and have a functional role in tumorgenesis. With the aim to explore differences in epigenetic regulation of SOX11 expression in normal versus neoplastic cells, we investigated methylation and histone modifications related to the SOX11 promoter and the possibility to induce re-expression using histone deacetylase (HDAC) or EZH2 inhibitors.MethodsThe epigenetic regulation of SOX11 was investigated in distinct non-malignant cell populations (n = 7) and neoplastic cell-lines (n = 42) of different cellular origins. DNA methylation was assessed using bisulfite sequencing, methylation-specific melting curve analysis, MethyLight and pyrosequencing. The presence of H3K27me3 was assessed using ChIP-qPCR. The HDAC inhibitors Vorinostat and trichostatin A were used to induce SOX11 in cell lines with no endogenous expression.ResultsThe SOX11 promoter shows a low degree of methylation and strong enrichment of H3K27me3 in non-malignant differentiated cells, independent of cellular origin. Cancers of the B-cell lineage are strongly marked by de novo methylation at the SOX11 promoter in SOX11 non-expressing cells, while solid cancer entities display a more varying degree of SOX11 promoter methylation. The silencing mark H3K27me3 was generally present at the SOX11 promoter in non-expressing cells, and an increased enrichment was observed in cancer cells with a low degree of SOX11 methylation compared to cells with dense methylation. Finally, we demonstrate that the HDAC inhibitors (vorinostat and trichostatin A) induce SOX11 expression in cancer cells with low levels of SOX11 methylation.ConclusionsWe show that SOX11 is strongly marked by repressive histone marks in non-malignant cells. In contrast, SOX11 regulation in neoplastic tissues is more complex involving both DNA methylation and histone modifications. The possibility to re-express SOX11 in non-methylated tissue is of clinical relevance, and was successfully achieved in cell lines with low levels of SOX11 methylation. In breast cancer patients, methylation of the SOX11 promoter was shown to correlate with estrogen receptor status, suggesting that SOX11 may be functionally re-expressed during treatment with HDAC inhibitors in specific patient subgroups.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1208-y) contains supplementary material, which is available to authorized users.

The SOX11 transcription factor is a critical regulator of basal-like breast cancer growth, invasion, and basal-like gene expression

“…One possibility is that SOX11 is methylated in normal adult mammary cells, and becomes hypomethylated in cancer, particularly Her2-positive and basal-like breast cancers. Hypomethylation of oncogenic genes has been associated with many cancer types [ 14 ]; and methylation has been shown to be associated with SOX11 expression in hematopoietic and solid tumors [ 15 , 16 ]. Therefore, we investigated methylation of CpG sites near the SOX11 genomic location.…”

DNA methylation contributes to silencing the expression of linc00086 in gastric cancer

“…DNA methylation is an important type of epigenetic modification, and has been reported to be involved in tumorigenesis. Previous studies have identified that DNA methylation changes may result in aberrant gene expression in cancer (16,17), and a number of them may be an early molecular marker (18,19). focus of the present study was on the silencing of linc00086 by DNA methylation in GC.…”

SOX11: friend or foe in tumor prevention and carcinogenesis?

“…Trichostatin A (TSA) and vorinostat (SAHA) are commonly used as histone deacetylase inhibitors, and increased expression of SOX11 can be observed in breast cancer, neuroblastoma, Burkitt lymphoma, and MCL by TSA and SAHA treatment via the inhibition of histone deacetylation. 14,66 Furthermore, the treatment of 5-aza-2’-deoxycytidine, a DNA methyltransferase inhibitor, can upregulate expression of SOX11 in the NPC cell line CNE2 and consequently inhibit growth and invasion of NPC. 17 Although the epigenetic regulation of SOX11 in cancer is complicated, the application of epigenetic agents targeting SOX11 may provide new options for cancer therapy, which urgently need further investigation.…”