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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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Gene Chip analysis reveal SOX11-induced regulation of Rb-E2F and TGF-β signaling pathways. Ingenuity Pathway Analysis identified the canonical pathway "Molecular Mechanisms in Cancer" as highly associated with the 3647 deregulated genes. Within this pathway RB-E2F (A and B) and TGF-β (C and D) signaling is regulated in a time-dependent manner as shown after 24 h (A and C) and 48 h (B and D) of ectopic SOX11-overexpression. The differentially regulated genes are marked in red or green when the mean fold change for GRANTA-519 and JEKO-1 was ≥1.2 or ≤1.2. The remaining differentially regulated genes, including genes with different kinetics in the two cell lines, are marked in grey.
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Figure 6: Gene Chip analysis reveal SOX11-induced regulation of Rb-E2F and TGF-β signaling pathways. Ingenuity Pathway Analysis identified the canonical pathway "Molecular Mechanisms in Cancer" as highly associated with the 3647 deregulated genes. Within this pathway RB-E2F (A and B) and TGF-β (C and D) signaling is regulated in a time-dependent manner as shown after 24 h (A and C) and 48 h (B and D) of ectopic SOX11-overexpression. The differentially regulated genes are marked in red or green when the mean fold change for GRANTA-519 and JEKO-1 was ≥1.2 or ≤1.2. The remaining differentially regulated genes, including genes with different kinetics in the two cell lines, are marked in grey.

Mentions: 4861 transcripts (see Additional File 2) were found to be differentially expressed in GRANTA-519 and JEKO-1 at either 24 or 48 h of ectopic SOX11-overexpression. These genes and corresponding mean fold change values for 24 and 48 h of SOX11-overexpression were imported into Ingenuity Pathway Analysis (IPA, Ingenuity Systems, Mountain view, CA). IPA analysis (Ingenuity Systems) recognized 3647 individual genes among the 4861 GeneChip transcripts and identified "cell cycle" as the main molecular function associated with SOX11-induced genes. The identified cell cycle-associated transcripts (n = 355) are marked with an asterisk in Additional File 2. The strong correlation between the differentially regulated genes and cell cycle function is consistent with the observed change in proliferation (Figure 5c) emphasizing the biological relevance of the differentially regulated genes in relation to MCL and SOX11. Furthermore, IPA analysis was used to identify the main canonical pathway associated with the differentially regulated genes. The identified pathway, "Molecular Mechnisms in Cancer", is shown in full in Supplementary Figure S1 for 24 h (S1a) and 48 h (S1b) of ectopic SOX11-overexpression. Sections of the canonical pathway are shown in Figure 6a-d. Among others, this includes the Rb-E2F signaling pathway, known to be of major importance in MCL [19].


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)

Gene Chip analysis reveal SOX11-induced regulation of Rb-E2F and TGF-β signaling pathways. Ingenuity Pathway Analysis identified the canonical pathway "Molecular Mechanisms in Cancer" as highly associated with the 3647 deregulated genes. Within this pathway RB-E2F (A and B) and TGF-β (C and D) signaling is regulated in a time-dependent manner as shown after 24 h (A and C) and 48 h (B and D) of ectopic SOX11-overexpression. The differentially regulated genes are marked in red or green when the mean fold change for GRANTA-519 and JEKO-1 was ≥1.2 or ≤1.2. The remaining differentially regulated genes, including genes with different kinetics in the two cell lines, are marked in grey.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Gene Chip analysis reveal SOX11-induced regulation of Rb-E2F and TGF-β signaling pathways. Ingenuity Pathway Analysis identified the canonical pathway "Molecular Mechanisms in Cancer" as highly associated with the 3647 deregulated genes. Within this pathway RB-E2F (A and B) and TGF-β (C and D) signaling is regulated in a time-dependent manner as shown after 24 h (A and C) and 48 h (B and D) of ectopic SOX11-overexpression. The differentially regulated genes are marked in red or green when the mean fold change for GRANTA-519 and JEKO-1 was ≥1.2 or ≤1.2. The remaining differentially regulated genes, including genes with different kinetics in the two cell lines, are marked in grey.
Mentions: 4861 transcripts (see Additional File 2) were found to be differentially expressed in GRANTA-519 and JEKO-1 at either 24 or 48 h of ectopic SOX11-overexpression. These genes and corresponding mean fold change values for 24 and 48 h of SOX11-overexpression were imported into Ingenuity Pathway Analysis (IPA, Ingenuity Systems, Mountain view, CA). IPA analysis (Ingenuity Systems) recognized 3647 individual genes among the 4861 GeneChip transcripts and identified "cell cycle" as the main molecular function associated with SOX11-induced genes. The identified cell cycle-associated transcripts (n = 355) are marked with an asterisk in Additional File 2. The strong correlation between the differentially regulated genes and cell cycle function is consistent with the observed change in proliferation (Figure 5c) emphasizing the biological relevance of the differentially regulated genes in relation to MCL and SOX11. Furthermore, IPA analysis was used to identify the main canonical pathway associated with the differentially regulated genes. The identified pathway, "Molecular Mechnisms in Cancer", is shown in full in Supplementary Figure S1 for 24 h (S1a) and 48 h (S1b) of ectopic SOX11-overexpression. Sections of the canonical pathway are shown in Figure 6a-d. Among others, this includes the Rb-E2F signaling pathway, known to be of major importance in MCL [19].

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