Pleiotropic function of SRY-related HMG box transcription factor 4 in regulation of tumorigenesis

Abstract

In addition to their critical roles in embryonic development, cell fate decision, and differentiation, members of Sox (Sry-related high-mobility group box) family of transcription factors including Sox4 have been implicated in various cancers. Multiple studies have revealed an increased expression along with specific oncogenic function of Sox4 in tumors, while others observed a reduced expression of Sox4 in different types of malignancies and suppression of tumor initiation or progression by this protein. More interestingly, the prognostic value of Sox4 is debated due to obvious differences between various reports as well as inconsistencies within specific studies. This review summarizes our current understanding of Sox4 expression pattern and its transcription-dependent, as well as transcription-independent, functions in tumor initiation or progression and its correlation with patient survival. We also discuss the existing discrepancies between different reports and their possible explanations.

Fig. 1

Structure of the human Sox4 protein, its binding partners, mutations and truncated isoform (S395X) detected in human lung cancer. GRR glycine-rich region, SRR serine-rich region, TAD transactivation domain

Fig. 2

Regulation of Sox4 expression. Expression of Sox4 is regulated at three distinct levels; transcriptional, post-transcriptional, and post-translational. PGs prostaglandin A2 and delta12-prostaglandin J2

Fig. 3

Comparative analysis of cDNA microarray studies of Sox4 target genes in prostate cancer, adenoid cystic carcinoma, bladder, and small cell lung cancer cell lines. Target genes whose expression was >two-fold changed after Sox4 overexpression [75, 79, 80] or knockdown [81, 83] and represented in at least two datasets were included in this analysis

Fig. 4

Regulation of gene expression by Sox4. So far, two modes of regulation of gene expression by Sox4 have been identified; transcriptional and post-translational. At the transcriptional level, Sox4 can act both as a transcription factor and repressor, depending on the gene or cell type of interest. This differential regulation of gene expression, which is discussed in the text, plays a very important role in oncogenic or tumor suppressive functions of Sox4. It should be noted that not all of the illustrated complexes are present in every type of cell