The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer†

Medina, Pedro P.; Castillo, Sandra D.; Blanco, Sandra; Sanz-García, Marta; Largo, Cristina; Álvarez, Sara; Yokota, Jun; González-Neira, Anna; Benı́tez, Javier; Clevers, Hans; Cigudosa, Juan C.; Lazo, Pedro A.; Sanchez-Cespedes, Montse

doi:10.1093/hmg/ddp034

Cited by 102 publications

(90 citation statements)

References 41 publications

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“…11,[28][29][30] The correlation of high SOX4 expression with poor clinical outcome ( Figure 6D-E) is novel and suggests that SOX4 and SOX4-mediated signaling represent a potential therapeutic target for patients with ALL.…”

Section: Discussionmentioning

confidence: 99%

SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia

Ramezani-Rad

Geng

Hurtz

et al. 2013

Blood

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• Sox4 is required for survival, progression, and proliferation in pre-B acute lymphoblastic leukemia.• Sox4 activates critical survival signaling pathways and correlates with poor clinical outcome. IntroductionThe Sox4 (SRY-related HMG-box) transcription factor is expressed in early B-and T-cell development similar to LEF1. 1 In the absence of Sox4, B-cell development is arrested at the pro-B to pre-B cell transition. 2 In Sox4 Ϫ/Ϫ mice, pro-B cells fail to proliferate in response to IL7 and to expand and differentiate past the pre-B cell receptor checkpoint. 2 Interestingly, SOX4 functions as transcription factor yet closely interacts with membrane-proximal cytokine receptor signaling. 3 The PDZ domain-containing adaptor protein syntenin (SDCBP) recruits the Sox4 protein directly to the cytoplasmic tail of the IL5R␣ chain. 3 With regard to its receptor-proximal activation, Sox4 resembles the SMAD and STAT transcription factors. In addition to its IL5R␣ interaction, Sox4/syntenin associates with the cytoplasmic tails of other transmembrane receptors, including syndecans and ephrins. 4,5 Because IL5R␣ signaling is dispensable for early B-cell development, the receptor system that recruits syntenin-mediated activation of Sox4 in early B-cell development remains to be identified. A role for Sox4 in acute myeloid leukemia was proposed based on the identification of viral insertions, activating Sox4 expression in leukemias developing in mice carrying endogenous retroviruses. 6 Overexpression of Sox4 was also found to block differentiation of myeloid progenitor cells. 7 Importantly, Sox4 overexpression causes myeloid leukemia 6 and thereby cooperates with haplo-insufficiency of the myeloid differentiation factor PU.1. 8 In acute lymphoblastic leukemia (ALL), we found SOX4 was strongly up-regulated on tyrosine kinase inhibitor (TKI) treatment and high expression of SOX4 correlates with poor clinical outcome of patients with ALL. However, the role of Sox4 in ALL cells remains unclear. In this study, using a conditional Sox4 knockout mouse model, we showed that the deletion of Sox4 compromised proliferation and viability of leukemia cells and that SOX4 plays as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL. Methods Pre-B and leukemia cell cultureThe work described here involves animal experiments (approved by Children's Hospital Los Angeles Institutional Animal Care and Use Committee) and analysis of clinical data (No Human Subjects, Exempt No. 4; IRB approval under Children's Oncology Group (COG) and Eastern Cooperative Oncology Group study protocols). Primary human leukemia cells were cultured on OP9 stroma cells in ␣ minimum essential medium without ribonucleotides and deoxyribonucleotides (MEM␣; Invitrogen), supplemented with 20% FBS, 2mM L-glutamine, 1mM sodium pyruvate, 100 IU/mL penicillin and 100 mg/mL streptomycin. Human ALL cell lines were maintained in RPMI with GlutaMAX (Invitrogen) containing 20% FBS, 100 IU/mL penicillin, and 100 mg/mL streptomycin. Mouse BCR-ABL1 transformed pre-B ce...

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Section: Discussionmentioning

confidence: 99%

SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia

Ramezani-Rad

Geng

Hurtz

et al. 2013

Blood

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“…Recently, an acquired stop mutant in the C-terminal serine-rich region of Sox4 (S395X) was found to be associated with a primary lung tumor (Medina et al, 2009). Interestingly, this Sox4 mutant demonstrated enhanced protein expression and, although it was not transcriptionally active, its ectopic expression modulated in vitro transformation of NIH-3T3 cells expressing the weakly oncogenic RhoA-Q63L mutant.…”

Section: Discussionmentioning

confidence: 99%

“…miRNA-mediated reduction in Sox4 expression has been shown to correlate with reduced breast cancer metastases in vivo, demonstrating a relation between Sox4 expression levels and cancer progression (Tavazoie et al, 2008). In addition, a recent study described somatic stop mutants of Sox4 in a primary lung tumor, and showed that Sox4 stop mutants associated with transforming ability in vitro and enhanced Sox4 protein levels (Medina et al, 2009). Induction of DNA damage has also been found to control Sox4 protein expression independent of its mRNA transcript levels, suggesting post-transcriptional regulation of Sox4 in response to DNA damage (Pan et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

et al. 2011

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The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitinindependent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.

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“…We began with a meta-analysis in public lung cancer gene expression databases inquiring if there is any unique expressing pattern among the SOX genes. In this regard, SOX4 was reported as a target of gene amplification in lung cancer (14); more intriguingly, the well-known embryonic regulator SOX2 was recently shown as an amplified lineage-specific survival oncogene for lung and esophagus SQC (15). Aside from these two genes, there has been no evidence linking other SOX family members with lung cancers.…”

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confidence: 99%

Upregulation of SOX9 in Lung Adenocarcinoma and Its Involvement in the Regulation of Cell Growth and Tumorigenicity

Jiang

Fang

Hou

et al. 2010

Clinical Cancer Research

109

118

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Purpose: SOX9 is an important transcription factor required for development and has been implicated in several types of cancer. However, SOX9 has never been linked to lung cancer to date. Here, we show that SOX9 expression is upregulated in lung adenocarcinoma and show how it is associated with cancer cell growth.Experimental Design: Data mining with five microarray data sets containing 490 clinical samples, quantitative reverse transcription-PCR validation assay in 57 independent samples, and immunohistochemistry assay with tissue microarrays containing 170 lung tissue cores were used to profile SOX9 mRNA and protein expression. Short interference RNA suppression of SOX9 in cell lines was used to scrutinize functional role(s) of SOX9 and associated molecular mechanisms.Results: SOX9 mRNA and protein were consistently overexpressed in the majority of lung adenocarcinoma. Knockdown of SOX9 in lung adenocarcinoma cell lines resulted in marked decrease of adhesive and anchorage-independent growth in concordance with the upregulation of p21 (CDKN1A) and downregulation of CDK4. In agreement with higher SOX9 expression level in lung adenocarcinoma, the p21 mRNA level was significantly lower in tumors than that in normal tissues, whereas the opposite was true for CDK4, supporting the notion that SOX9 negatively and positively regulated p21 and CDK4, respectively. Finally, whereas SOX9-knockdown cells showed significantly attenuated tumorigenicity in mice, SOX9 transfectants consistently showed markedly stronger tumorigenicity.Conclusions: Our data suggest that SOX9 is a new hallmark of lung adenocarcinoma, in which SOX9 might contribute to gain of tumor growth potential, possibly acting through affecting the expression of cell cycle regulators p21 and CDK4. Clin Cancer Res; 16(17); 4363-73. ©2010 AACR.Lung cancer is currently the most common malignancy and the leading cause of cancer death in the world (1). Clinically, non-small cell lung carcinoma (NSCLC) represents >80% of lung cancers and can be classified into adenocarcinoma (ADC), squamous cell carcinoma (SQC), and large cell carcinoma. ADC and SQC constitutes two major subtypes of NSCLC, and there is a trend that incidence of ADC is increasing worldwide, particularly in women (2, 3). In addition, ADC is the most common histologic types of lung cancers arising in never and former smokers (4, 5). The 5-year survival rate for all stages of NSCLC patients is only ∼15%, majorly due to diagnosis at late stage when tumor has progressed and become inoperable. Given the life-threatening nature of lung cancers, it is important to identify biomarkers for their early detection and prognosis, and to obtain a better understanding of the underlying mechanisms with respect to the functional roles of the molecules involved in the development and advances of the cancer. Although many markers from gene expression profiling analysis of lung cancers have Authors' Affiliations:

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The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer†

Cited by 102 publications

References 41 publications

SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia

SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

Upregulation of SOX9 in Lung Adenocarcinoma and Its Involvement in the Regulation of Cell Growth and Tumorigenicity

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