Knockdown of Sox4 expression by RNAi induces apoptosis in ACC3 cells

Pramoonjago, Patcharin; Baras, Alexander S.; Moskaluk, Christopher A.

doi:10.1038/sj.onc.1209566

Cited by 88 publications

(75 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fourteen genes with sixfold higher expression in the T3 tissues were identified and these were enriched with adhesion molecules (NRCAM, CD24, CTHRC1 and ROBO1) and transcription factors (FOXQ1, CDCA7 L, MYBL2 and SOX4); thus, these genes are candidate genes for direct involvement in tumor metastasis (Figures 1a and b). Overexpression of SOX4 has been shown to promote apoptosis in bladder carcinoma (Aaboe et al, 2006); in contrast, RNAi knockdown of SOX4 induces apoptosis in adenoid cystic carcinoma and prostate cancer (Liu et al, 2006;Pramoonjago et al, 2006). This suggests that the SOX4 molecular activity during caracinogenesis is influenced by additional factors that are enriched in a tissuespecific manner.…”

Section: Identification Of Genes Associated With Intrahepatic Metastamentioning

confidence: 81%

“…Empirical evidence suggested that SOX4 plays an important function in liver tumor metastasis as RNAi knockdown reduced HCC cell migration, invasion and intrahepatic metastasis in an orthotopic liver cancer model. This SOX4 function also seems to operate during breast cancer metastasis (Tavazoie et al, 2008) but not in other human cancer types (Aaboe et al, 2006;Liu et al, 2006;Pramoonjago et al, 2006). This suggests that SOX4 has diverse activities across various human cancers and that these are likely to be cell context-dependent, involving differential target activation.…”

Section: Discussionmentioning

confidence: 98%

“…SOX4 is absent in adult normal livers (Hunt and Clarke, 1999), hence it is not involved in normal liver functions. Recently, overexpression of SOX4 has been found to be associated with several human cancer types (Aaboe et al, 2006;Liu et al, 2006;Pramoonjago et al, 2006). Although SOX4 was the first 'classical' transcription factor identified with separable DNA-binding and transactivation domains among the SOX family members, information on its target genes is scanty.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma

Yl¹,

et al. 2008

View full text Add to dashboard Cite

A comprehensive microarray analysis of hepatocellular carcinoma (HCC) revealed distinct synexpression patterns during intrahepatic metastasis. Recent evidence has demonstrated that synexpression group member genes are likely to be regulated by master control gene(s). Here we investigate the functions and gene regulation of the transcription factor SOX4 in intrahepatic metastatic HCC. SOX4 is important in tumor metastasis as RNAi knockdown reduces tumor cell migration, invasion, in vivo tumorigenesis and metastasis. A multifaceted approach integrating gene profiling, binding site computation and empirical verification by chromatin immunoprecipitation and gene ablation refined the consensus SOX4 binding motif and identified 32 binding loci in 31 genes with high confidence. RNAi knockdown of two SOX4 target genes, neuropilin 1 and semaphorin 3C, drastically reduced cell migration activity in HCC cell lines suggesting that SOX4 exerts some of its action via regulation of these two downstream targets. The discovery of 31 previously unidentified targets expands our knowledge of how SOX4 modulates HCC progression and implies a range of novel SOX4 functions. This integrated approach sets a paradigm whereby a subset of member genes from a synexpression group can be regulated by one master control gene and this is exemplified by SOX4 and advanced HCC.

show abstract

Section: Identification Of Genes Associated With Intrahepatic Metastamentioning

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma

Yl¹,

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Nevertheless, SOX4 was also reported to be an oncogene for human prostate cancer cells (45), and SOX4 knockdown promotes apoptosis in adenoid cystic carcinoma cells (46). Thus, whether SOX4 is a tumor suppressor or an oncogene is presumably context-dependent, which is worth further investigation.…”

Section: Discussionmentioning

confidence: 99%

Induction of SOX4 by DNA damage is critical for p53 stabilization and function

Pan

Zhao²,

Zhang³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

124

113

View full text Add to dashboard Cite

DNA damage response (DDR) acts as a tumorigenesis barrier, and any defects in the DDR machinery may lead to cancer. SOX4 expression is elevated in many types of tumors; however, its role in DDR is still largely unknown. Here, we show that SOX4, a new DNA damage sensor, is required for the activation of p53 tumor suppressor in response to DNA damage. Notably, SOX4 interacts with and stabilizes p53 protein by blocking Mdm2-mediated p53 ubiquitination and degradation. Furthermore, SOX4 enhances p53 acetylation by interacting with p300/CBP and facilitating p300/CBP/p53 complex formation. In concert with these results, SOX4 promotes cell cycle arrest and apoptosis, and it inhibits tumorigenesis in a p53-dependent manner. Therefore, these findings highlight SOX4 as a potential key factor in regulating DDR-associated cancer.Mdm2 ͉ ubiquitination ͉ tumorigenesis D NA damage response (DDR), a highly conserved response to genotoxic stresses, is the guardian of genomic integrity (1, 2). It has been shown that DDR serves as a barrier to constrain tumor progression in its early stages by inducing cell cycle arrest, DNA repair, or apoptosis (3). A number of components are involved in cellular DDR machinery, in which ATM-Chk2-p53 and ATRChk1-p53 cascade are the key signaling pathways involved (2). A central component of DDR, p53, is one of the most important tumor suppressor proteins (4-8). The major consequence of p53 activation upon DNA damage is the induction of specific target genes, such as p21 WAF , Bax, and Puma, to initiate cell cycle arrest, apoptosis, and DNA repair (4). Cells lacking functional p53 exhibit a partial deficiency in DNA damage repair, resulting in uncontrolled cell proliferation and malignancy. Indeed, p53 gene is either lost or mutated in more than half of all human cancers (9). Around p53 there is a highly regulated network consisting of numerous proteins that interact with p53 and regulate its activity by protein stabilization, posttranscriptional modifications, protein-protein interaction, and protein subcellular localization (10), among which stabilization of p53 is presumed to play a major role in its activation. Under normal conditions, amount and activity of p53 are maintained at low levels by Mdm2, a ubiquitin E3 ligase, which binds to the N terminus of p53 and targets its C-terminal lysine residues for ubiquitination and degradation (11,12). However, in response to DNA damage, p53 protein is rapidly stabilized and activated mostly through multiple posttranslational modifications, such as phosphorylation and acetylation of specific residues in the N-terminal and C-terminal domains. DNA damage-induced p53 phosphorylation, which is mediated by ATM kinase (13, 14), contributes to p53 stability (15). Acetylation of p53 C-terminal lysine residues in p53 stabilizes the protein by preventing Mdm2-mediated ubiquitination of the same residues (16,17). In addition, the activity of p53 is also modulated by its recruitment of transcriptional coactivators or corepressors.SOX4 is a member of the SOX (SRY-re...

show abstract

“…SOX4 has been shown to be a transcriptional activator in lymphocytes (van de Wetering et al, 1993) and facilitates B and T cell differentiation (Schilham et al, 1996;Schilham et al, 1997). SOX4 gene expression is up-regulated in many tumor types, with experimental evidence suggesting that this contributes to cellular transformation (Liu et al, 2006;Shin et al, 2004), control of apoptosis (Liu et al, 2006;Pramoonjago et al, 2006;Aaboe et al, 2006;Ahn et al, 2002) and/or a metastatic phenotype (Liao et al, 2008;Tavazoie et al, 2008).…”

Section: Functionmentioning

confidence: 99%