The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe?

Abstract

Development and progression of cancer are mediated by alterations in transcriptional networks, resulting in a disturbed balance between the activity of oncogenes and tumor suppressor genes. Transcription factors have the capacity to regulate global transcriptional profiles, and are consequently often found to be deregulated in their expression and function during tumorigenesis. Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) is a member of the group C subfamily of the SOX transcription factors and has a critical role during embryogenesis, where its expression is widespread and controls the development of numerous tissues. SOX4 expression is elevated in a wide variety of tumors, including leukemia, colorectal cancer, lung cancer and breast cancer, suggesting a fundamental role in the development of these malignancies. In many cancers, deregulated expression of this developmental factor has been correlated with increased cancer cell proliferation, cell survival, inhibition of apoptosis and tumor progression through the induction of an epithelial-to-mesenchymal transition and metastasis. However, in a limited subset of tumors, SOX4 has also been reported to act as a tumor suppressor. These opposing roles suggest that the outcome of SOX4 activation depends on the cellular context and the tumor origin. Indeed, SOX4 expression, transcriptional activity and target gene specificity can be controlled by signaling pathways, including the transforming growth factor-β and the WNT pathway, as well as at the post-translational level through regulation of protein stability and interaction with specific cofactors, such as TCF, syntenin-1 and p53. Here, we provide an overview of our current knowledge concerning the role of SOX4 in tumor development and progression.

SOX4 induces tumor invasion by targeting EMT-related pathway in prostate cancer

“…[9][10][11] In this study, we investigated the expression of SOX4 in a series of clinical PCa tissues. The IHC analysis showed that SOX4 staining was stronger in PCa tissues than in adjacent tissue.…”

The Sox4/Tcf7l1 axis promotes progression of BCR-ABL-positive acute lymphoblastic leukemia

“…However, the role of SOX4 in different tumor types remains controversial. 4 For example, SOX4 has been shown to function as an oncogene in prostate, colorectal, and breast cancers, by inducing and maintaining cancer-initiating cells, supporting cancer cell survival, and promoting cancer cell invasion and metastasis. In contrast, increased SOX4 expression was also shown to correlate with prolonged survival and slower disease progression in patients with bladder carcinoma, gallbladder carcinoma, and medulloblastoma, suggesting that SOX4 can have a tumor-suppressor role.…”

Krüppel-Like Factor 5 Promotes Lung Tumorigenesis through Upregulation of Sox4

“…Sox4, a member of SOX (Sry-box) family known, is initially implied in the development of the cardiac outflow tract, pro-B cell expansion and the central nervous system [25,26]. Subsequent studies reveal that Sox4 expression is positively correlated with progression of several human cancer types, suggesting that its overexpression might be a useful prognostic marker for cancers [27]. For instance, Sox4 induces epithelial-mesenchymal transition and contributes to breast cancer progression, by controlling Ezh2 expression and epigenetic reprogramming [28,29].…”