Limits...
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.

Show MeSH

Related in: MedlinePlus

SOX11 DNA methylation and protein expression in primary lymphoma samples. Methylation patterns of SOX11 promoter in clinical specimens was determined by bisulfite sequencing of individual alleles and correlated to SOX11 protein expression. Every row represents a unique allele and the columns represent a potentially methylated CpG site. a) In MCL samples, the promoter stays unmethylated and SOX11 is detectable. b) The lack of SOX11 protein in FL and DLBCL is accompanied by 50-100% methylated alleles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2913986&req=5

Figure 3: SOX11 DNA methylation and protein expression in primary lymphoma samples. Methylation patterns of SOX11 promoter in clinical specimens was determined by bisulfite sequencing of individual alleles and correlated to SOX11 protein expression. Every row represents a unique allele and the columns represent a potentially methylated CpG site. a) In MCL samples, the promoter stays unmethylated and SOX11 is detectable. b) The lack of SOX11 protein in FL and DLBCL is accompanied by 50-100% methylated alleles.

Mentions: In agreement with the in vitro data a difference in DNA methylation status of the SOX11 promoter was evident between expressing and non-expressing primary B cell lymphomas. The SOX11 promoter was not methylated in primary MCL (Figure 3A), which was consistent with protein analysis (Figure 3A lower panel). However, extensive (>70%) DNA methylation was seen in the DLBCL and FL samples, apart from FL5 where less (50%) of the alleles were methylated (Figure 3B, upper panel), possibly due to a sub-population of non-malignant cells. As expected, none of the primary FL or DLBCL samples expressed the SOX11 protein (Figure 3B, lower panel). This is in agreement with both previous gene expression data [1] and current RT-PCR data on DLBCL cell lines (Figure 2) and thus confirms that the cytoplasmic staining seen in IHC for DLBCL and other non-MCLs [1,3-5,18] should not be considered to be specific for SOX11.


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)

SOX11 DNA methylation and protein expression in primary lymphoma samples. Methylation patterns of SOX11 promoter in clinical specimens was determined by bisulfite sequencing of individual alleles and correlated to SOX11 protein expression. Every row represents a unique allele and the columns represent a potentially methylated CpG site. a) In MCL samples, the promoter stays unmethylated and SOX11 is detectable. b) The lack of SOX11 protein in FL and DLBCL is accompanied by 50-100% methylated alleles.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: SOX11 DNA methylation and protein expression in primary lymphoma samples. Methylation patterns of SOX11 promoter in clinical specimens was determined by bisulfite sequencing of individual alleles and correlated to SOX11 protein expression. Every row represents a unique allele and the columns represent a potentially methylated CpG site. a) In MCL samples, the promoter stays unmethylated and SOX11 is detectable. b) The lack of SOX11 protein in FL and DLBCL is accompanied by 50-100% methylated alleles.
Mentions: In agreement with the in vitro data a difference in DNA methylation status of the SOX11 promoter was evident between expressing and non-expressing primary B cell lymphomas. The SOX11 promoter was not methylated in primary MCL (Figure 3A), which was consistent with protein analysis (Figure 3A lower panel). However, extensive (>70%) DNA methylation was seen in the DLBCL and FL samples, apart from FL5 where less (50%) of the alleles were methylated (Figure 3B, upper panel), possibly due to a sub-population of non-malignant cells. As expected, none of the primary FL or DLBCL samples expressed the SOX11 protein (Figure 3B, lower panel). This is in agreement with both previous gene expression data [1] and current RT-PCR data on DLBCL cell lines (Figure 2) and thus confirms that the cytoplasmic staining seen in IHC for DLBCL and other non-MCLs [1,3-5,18] should not be considered to be specific for SOX11.

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