Multi-Omics Analysis of SOX4, SOX11, and SOX12 Expression and the Associated Pathways in Human Cancers

The Sry-related HMG BOX (SOX) gene family encodes transcription factors containing highly conserved high-mobility group domains that bind to the minor groove in DNA. Although some SOX genes are known to be associated with tumorigenesis and cancer progression, their expression and prognostic value have not been systematically studied. We performed multi-omic analysis to investigate the expression of SOX genes in human cancers. Expression and phylogenetic tree analyses of the SOX gene family revealed that the expression of three closely related SOX members, SOX4, SOX11, and SOX12, was increased in multiple cancers. Expression, mutation, and alteration of the three SOX members were evaluated using the Oncomine and cBioPortal databases, and the correlation between these genes and clinical outcomes in various cancers was examined using the Kaplan–Meier, PrognoScan, and R2 database analyses. The genes commonly correlated with the three SOX members were categorized in key pathways related to the cell cycle, mitosis, immune system, and cancer progression in liver cancer and sarcoma. Additionally, functional protein partners with three SOX proteins and their probable signaling pathways were explored using the STRING database. This study suggests the prognostic value of the expression of three SOX genes and their associated pathways in various human cancers.

Alternate Roles of Sox Transcription Factors beyond Transcription Initiation

Sox proteins are known as crucial transcription factors for many developmental processes and for a wide range of common diseases. They were believed to specifically bind and bend DNA with other transcription factors and elicit transcriptional activation or repression activities in the early stage of transcription. However, their functions are not limited to transcription initiation. It has been showed that Sox proteins are involved in the regulation of alternative splicing regulatory networks and translational control. In this review, we discuss the current knowledge on how Sox transcription factors such as Sox2, Sry, Sox6, and Sox9 allow the coordination of co-transcriptional splicing and also the mechanism of SOX4-mediated translational control in the context of RNA polymerase III.

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

The SOX proteins belong to the superfamily of transcription factors (TFs) that display properties of both classical TFs and architectural components of chromatin. Since the cloning of the Sox/SOX genes, remarkable progress has been made in illuminating their roles as key players in the regulation of multiple developmental and physiological processes. SOX TFs govern diverse cellular processes during development, such as maintaining the pluripotency of stem cells, cell proliferation, cell fate decisions/germ layer formation as well as terminal cell differentiation into tissues and organs. However, their roles are not limited to development since SOX proteins influence survival, regeneration, cell death and control homeostasis in adult tissues. This review summarized current knowledge of the roles of SOX proteins in control of central nervous system development. Some SOX TFs suspend neural progenitors in proliferative, stem-like state and prevent their differentiation. SOX proteins function as pioneer factors that occupy silenced target genes and keep them in a poised state for activation at subsequent stages of differentiation. At appropriate stage of development, SOX members that maintain stemness are down-regulated in cells that are competent to differentiate, while other SOX members take over their functions and govern the process of differentiation. Distinct SOX members determine down-stream processes of neuronal and glial differentiation. Thus, sequentially acting SOX TFs orchestrate neural lineage development defining neuronal and glial phenotypes. In line with their crucial roles in the nervous system development, deregulation of specific SOX proteins activities is associated with neurodevelopmental disorders (NDDs). The overview of the current knowledge about the link between SOX gene variants and NDDs is presented. We outline the roles of SOX TFs in adult neurogenesis and brain homeostasis and discuss whether impaired adult neurogenesis, detected in neurodegenerative diseases, could be associated with deregulation of SOX proteins activities. We present the current data regarding the interaction between SOX proteins and signaling pathways and microRNAs that play roles in nervous system development. Finally, future research directions that will improve the knowledge about distinct and various roles of SOX TFs in health and diseases are presented and discussed.

MicroRNAs regulating SOX2 in cancer progression and therapy response

The proliferation, metastasis and therapy response of tumour cells are tightly regulated by interaction among various signalling networks. The microRNAs (miRNAs) can bind to 3′-UTR of mRNA and down-regulate expression of target gene. The miRNAs target various molecular pathways in regulating biological events such as apoptosis, differentiation, angiogenesis and migration. The aberrant expression of miRNAs occurs in cancers and they have both tumour-suppressor and tumour-promoting functions. On the contrary, SOX proteins are capable of binding to DNA and regulating gene expression. SOX2 is a well-known member of SOX family that its overexpression in different cancers to ensure progression and stemness. The present review focuses on modulatory impact of miRNAs on SOX2 in affecting growth, migration and therapy response of cancers. The lncRNAs and circRNAs can function as upstream mediators of miRNA/SOX2 axis in cancers. In addition, NF-κB, TNF-α and SOX17 are among other molecular pathways regulating miRNA/SOX2 axis in cancer. Noteworthy, anti-cancer compounds including bufalin and ovatodiolide are suggested to regulate miRNA/SOX2 axis in cancers. The translation of current findings to clinical course can pave the way to effective treatment of cancer patients and improve their prognosis.

The SOXE transcription factors—SOX8, SOX9 and SOX10—share a bi-partite transactivation mechanism

SOX8, SOX9 and SOX10 compose the SOXE transcription factor group. They govern cell fate and differentiation in many lineages, and mutations impairing their activity cause severe diseases, including campomelic dysplasia (SOX9), sex determination disorders (SOX8 and SOX9) and Waardenburg-Shah syndrome (SOX10). However, incomplete knowledge of their modes of action limits disease understanding. We here uncover that the proteins share a bipartite transactivation mechanism, whereby a transactivation domain in the middle of the proteins (TAM) synergizes with a C-terminal one (TAC). TAM comprises amphipathic α-helices predicted to form a protein-binding pocket and overlapping with minimal transactivation motifs (9-aa-TAD) described in many transcription factors. One 9-aa-TAD sequence includes an evolutionarily conserved and functionally required EΦ[D/E]QYΦ motif. SOXF proteins (SOX7, SOX17 and SOX18) contain an identical motif, suggesting evolution from a common ancestor already harboring this motif, whereas TAC and other transactivating SOX proteins feature only remotely related motifs. Missense variants in this SOXE/SOXF-specific motif are rare in control individuals, but have been detected in cancers, supporting its importance in development and physiology. By deepening understanding of mechanisms underlying the central transactivation function of SOXE proteins, these findings should help further decipher molecular networks essential for development and health and dysregulated in diseases.

Crazy Little Thing Called Sox—New Insights in Oligodendroglial Sox Protein Function

In the central nervous system, oligodendrocytes wrap axons with myelin sheaths, which is essential for rapid transfer of electric signals and their trophic support. In oligodendroglia, transcription factors of the Sox protein family are pivotal regulators of a variety of developmental processes. These include specification, proliferation, and migration of oligodendrocyte precursor cells as well as terminal differentiation to mature myelinating oligodendrocytes. Sox proteins are further affected in demyelinating diseases and are involved in remyelination following damage of the central nervous system. Here we summarize and discuss latest findings on transcriptional regulation of Sox proteins, their function, target genes, and interaction with other transcription factors and chromatin remodelers in oligodendroglia with physiological and pathophysiological relevance.