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SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies.

Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M, Borrebaeck CA, Ek S - Mol. Cancer (2010)

Bottom Line: Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction.The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation.Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunotechnology, Lund University, Lund, Sweden.

ABSTRACT

Background: The transcription factor SOX11 plays an important role in embryonic development of the central nervous system (CNS) and is expressed in the adult immature neuron but is normally not expressed in any other adult tissue. It has recently been reported to be implicated in various malignant neoplasms, including several lymphoproliferative diseases, by its specific expression and in some cases correlation to prognosis. SOX11 has been shown to prevent gliomagenesis in vivo but the causes and consequences of aberrant expression of SOX11 outside the CNS remain unexplained.

Results: We now show the first function of SOX11 in lymphoproliferative diseases, by demonstrating in vitro its direct involvement in growth regulation, as assessed by siRNA-mediated silencing and ectopic overexpression in hematopoietic malignancies. Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction. Furthermore, promoter analysis revealed that SOX11 is silenced through DNA methylation in B cell lymphomas, suggesting that its regulation is epigenetically controlled.

Conclusions: The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation. Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

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CpG islands in the SOX11 promoter region. Analysis of 2000 bp upstream of SOX11 transcription start revealed four CpG islands with a GC content above 50 percent http://www.urogene.org/methprimer/index1.html [45]. CpG dinucleotides are represented as vertical bars. Primers that amplified -435 to -222 were used in bisulfite sequencing to compare the methylation status of the SOX11 promoter region with SOX11 expression.
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Figure 1: CpG islands in the SOX11 promoter region. Analysis of 2000 bp upstream of SOX11 transcription start revealed four CpG islands with a GC content above 50 percent http://www.urogene.org/methprimer/index1.html [45]. CpG dinucleotides are represented as vertical bars. Primers that amplified -435 to -222 were used in bisulfite sequencing to compare the methylation status of the SOX11 promoter region with SOX11 expression.

Mentions: Epigenetic regulation of SOX11 expression was investigated by studying promoter methylation. Analysis of the 2000 bp region upstream of the transcription start site of SOX11 identified four CpG islands (Figure 1). DNA hypermethylation of such islands is a common event in tumor progression and leads to silencing of the corresponding gene [17]. The methylation status of the SOX11 promoter was assessed in nineteen cell lines, originating from different B cell malignancies, including eight MCL, three DLBCL, four FL, three BL and one acute monocytic leukemia (MONO-L) (Table 1). Initially, seven cell lines were assessed for presence of methylated CpGs in all four identified CpG islands (Figure 1). However only the CpG island closest to transcription start was determinative for SOX11 expression in all seven cell lines (data not shown), thus in the remaining analyses bisulfite sequencing was performed on the CpG island adjacent to the SOX11 transcription start site, covering 28 unique CpG sites (Figure 1).


SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies.

Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M, Borrebaeck CA, Ek S - Mol. Cancer (2010)

CpG islands in the SOX11 promoter region. Analysis of 2000 bp upstream of SOX11 transcription start revealed four CpG islands with a GC content above 50 percent http://www.urogene.org/methprimer/index1.html [45]. CpG dinucleotides are represented as vertical bars. Primers that amplified -435 to -222 were used in bisulfite sequencing to compare the methylation status of the SOX11 promoter region with SOX11 expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913986&req=5

Figure 1: CpG islands in the SOX11 promoter region. Analysis of 2000 bp upstream of SOX11 transcription start revealed four CpG islands with a GC content above 50 percent http://www.urogene.org/methprimer/index1.html [45]. CpG dinucleotides are represented as vertical bars. Primers that amplified -435 to -222 were used in bisulfite sequencing to compare the methylation status of the SOX11 promoter region with SOX11 expression.
Mentions: Epigenetic regulation of SOX11 expression was investigated by studying promoter methylation. Analysis of the 2000 bp region upstream of the transcription start site of SOX11 identified four CpG islands (Figure 1). DNA hypermethylation of such islands is a common event in tumor progression and leads to silencing of the corresponding gene [17]. The methylation status of the SOX11 promoter was assessed in nineteen cell lines, originating from different B cell malignancies, including eight MCL, three DLBCL, four FL, three BL and one acute monocytic leukemia (MONO-L) (Table 1). Initially, seven cell lines were assessed for presence of methylated CpGs in all four identified CpG islands (Figure 1). However only the CpG island closest to transcription start was determinative for SOX11 expression in all seven cell lines (data not shown), thus in the remaining analyses bisulfite sequencing was performed on the CpG island adjacent to the SOX11 transcription start site, covering 28 unique CpG sites (Figure 1).

Bottom Line: Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction.The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation.Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunotechnology, Lund University, Lund, Sweden.

ABSTRACT

Background: The transcription factor SOX11 plays an important role in embryonic development of the central nervous system (CNS) and is expressed in the adult immature neuron but is normally not expressed in any other adult tissue. It has recently been reported to be implicated in various malignant neoplasms, including several lymphoproliferative diseases, by its specific expression and in some cases correlation to prognosis. SOX11 has been shown to prevent gliomagenesis in vivo but the causes and consequences of aberrant expression of SOX11 outside the CNS remain unexplained.

Results: We now show the first function of SOX11 in lymphoproliferative diseases, by demonstrating in vitro its direct involvement in growth regulation, as assessed by siRNA-mediated silencing and ectopic overexpression in hematopoietic malignancies. Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction. Furthermore, promoter analysis revealed that SOX11 is silenced through DNA methylation in B cell lymphomas, suggesting that its regulation is epigenetically controlled.

Conclusions: The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation. Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

Show MeSH
Related in: MedlinePlus