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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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Related in: MedlinePlus

Methylation status of SOX11 promoter region correlated to SOX11 expression. Methylation status of SOX11 promoter (described as percentage of methylated CpGs of 28 possible CpG methylation sites) was analyzed by direct bisulfite sequencing (right Y-axis) and correlated to SOX11 expression on mRNA (left Y-axis) and protein level in nineteen lymphoid or monocytic cell lines (Table 1). Generally, all samples with a ΔCT (SOX11+RT, SOX11-RT) < /2/ was considered negative and the RQ was set to 0.01 for those samples. RQ values are related to the SOX11 expression in GRANTA-519 and the error bars show the 95% confidence interval
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Figure 2: Methylation status of SOX11 promoter region correlated to SOX11 expression. Methylation status of SOX11 promoter (described as percentage of methylated CpGs of 28 possible CpG methylation sites) was analyzed by direct bisulfite sequencing (right Y-axis) and correlated to SOX11 expression on mRNA (left Y-axis) and protein level in nineteen lymphoid or monocytic cell lines (Table 1). Generally, all samples with a ΔCT (SOX11+RT, SOX11-RT) < /2/ was considered negative and the RQ was set to 0.01 for those samples. RQ values are related to the SOX11 expression in GRANTA-519 and the error bars show the 95% confidence interval

Mentions: A striking difference in SOX11 promoter methylation was detected between MCL and non-MCL lymphoma cell lines (Figure 2). The results were confirmed on individual alleles with TOPO-TA cloning for seven of the cell lines (Table 1). Analysis of non-MCL cell lines revealed high levels of SOX11 promoter methylation in all cases (11/11), corresponding to a lack of both SOX11 mRNA and protein expression (Figure 2). In contrast, SOX11 promoter methylation was absent in the majority (7/8) of MCL-derived cell lines, with SOX11 mRNA and protein expression being evident in 6 of the cell lines (GRANTA-519, HBL-2, JEKO-1, REC-1, SP53 and Z138) (Figure 2). UPN-2 was partially methylated, and lacks SOX11 expression. JVM-2 was the only MCL cell line lacking SOX11 mRNA and protein, although the promoter was not methylated in any of the 28 CpG's investigated.


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)

Methylation status of SOX11 promoter region correlated to SOX11 expression. Methylation status of SOX11 promoter (described as percentage of methylated CpGs of 28 possible CpG methylation sites) was analyzed by direct bisulfite sequencing (right Y-axis) and correlated to SOX11 expression on mRNA (left Y-axis) and protein level in nineteen lymphoid or monocytic cell lines (Table 1). Generally, all samples with a ΔCT (SOX11+RT, SOX11-RT) < /2/ was considered negative and the RQ was set to 0.01 for those samples. RQ values are related to the SOX11 expression in GRANTA-519 and the error bars show the 95% confidence interval
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Methylation status of SOX11 promoter region correlated to SOX11 expression. Methylation status of SOX11 promoter (described as percentage of methylated CpGs of 28 possible CpG methylation sites) was analyzed by direct bisulfite sequencing (right Y-axis) and correlated to SOX11 expression on mRNA (left Y-axis) and protein level in nineteen lymphoid or monocytic cell lines (Table 1). Generally, all samples with a ΔCT (SOX11+RT, SOX11-RT) < /2/ was considered negative and the RQ was set to 0.01 for those samples. RQ values are related to the SOX11 expression in GRANTA-519 and the error bars show the 95% confidence interval
Mentions: A striking difference in SOX11 promoter methylation was detected between MCL and non-MCL lymphoma cell lines (Figure 2). The results were confirmed on individual alleles with TOPO-TA cloning for seven of the cell lines (Table 1). Analysis of non-MCL cell lines revealed high levels of SOX11 promoter methylation in all cases (11/11), corresponding to a lack of both SOX11 mRNA and protein expression (Figure 2). In contrast, SOX11 promoter methylation was absent in the majority (7/8) of MCL-derived cell lines, with SOX11 mRNA and protein expression being evident in 6 of the cell lines (GRANTA-519, HBL-2, JEKO-1, REC-1, SP53 and Z138) (Figure 2). UPN-2 was partially methylated, and lacks SOX11 expression. JVM-2 was the only MCL cell line lacking SOX11 mRNA and protein, although the promoter was not methylated in any of the 28 CpG's investigated.

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