ReviewTranscription factors in SOX family: Potent regulators for cancer initiation and development in the human body
Introduction
Cancer is a state of an abnormal cell proliferation that results from an alteration in gene regulation or the correct functioning of proteins, that are important for regulating cell growth and differentiation [1]. A cancer cell acquires profound metabolic and behavioural changes in a multi-step process. It is evident that genome instability, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, sustaining proliferative signalling, activating invasion and metastasis, inflammation, reprogramming of energy metabolism and evading immune destruction are the key characteristics of cancer cells [2]. Additionally, human malignancies, known to date, are often results of somatic gene alterations originated either through loss-of-function mutations in tumour suppressor genes or gain-of-function mutations in proto-oncogenes. However, we still do not understand the precise molecular mechanisms of cancer even after remarkable progress in cancer research in recent decades.
Transcription factors (TF) are proteins that have DNA binding domains, and that participate, alone or as part of a complex, in the binding to an enhancer cognate element or to the promoter that regulates an associated gene [3]. Therefore, genes which express TFs are involved in the regulation of gene expression. It is reported that around 2000 different TF-coding genes are encoded in the human genome, many of which are expressed in a cell type-specific manner to synchronize gene expression programs underlying an array of cellular processes [4]. It is often noticed that human cancer cells show a trend of deregulation of genes encoding TFs. Significantly, the tumour suppressor protein 53 (p53), encoded by TP53 and TF c-Myc, encoded by MYC, show drastic and dramatic changes in expression level across all cancers [5,6]. In the last decade, there has been an unprecedented growth in the understanding of the roles of TFs in the molecular mechanism associated with gene regulation in cancer cells and its treatment such as the case of FOXO1 in treating digestive malignancy [7]. In this context, the Sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family that comprises more than 20 members is of interest, as many SOX family members have potent roles as regulators of different human cancer types.
The mammalian testis-determining factor, SRY(Sex-determining Region of the Y chromosome), was the first gene discovered as one member of the SOX gene family [8,9]. SRY has a characteristic high-mobility-group (HMG) domain that binds DNA in a sequence-specific manner. Apart from SRY, Sinclair et al. further identified four additional SRY-related genes that contain a homologous region of 79 amino acids, 42 of them identical to that of SRY and assigned their names as a1 to a4 where a denotes ‘autosomal’ because none of them was associated to the Y chromosome [9]. Afterward, these SRY-related proteins were renamed SOX because of the presence of the SRY-related HMG box containing 79 C-terminal amino acid residues, which shows binding affinity to the same core sequence recognised by Tcf-1, that is, AACAAAG [10,11].
In general, an amino acid sequence with 50% or higher identity to the HMG domain of Sry is the decisive identification for a TF to be referred to as SOX protein (Sry-related HMG box). To date, 20 different genes encoding SOX proteins have been identified in mice and humans [12]. Additionally, the identification of two SOX-like genes in the unicellular choanoflagellate Monosiga brevicollis suggests that the SOX protein origin predates multicellularity or possibly transits from unicellular to multicellular organisms [13,14].
Several SOX subgroups are created from SOX proteins that share an HMG domain with more than 80% sequence identity, and those subgroups are named as SOX A to H based on phylogenetically analysed HMG box domains. In mammals, all SOX genes are classified into a total of eight groups from A to H: A (Sry), which is only present in mammals, B1 (SOX1, -2 and -3), B2 (SOX14 and -21), C (SOX4, -11 and -12), D (SOX5, -6 and -13), E (SOX8, -9 and -10), F (SOX7, -17 and -18), G (SOX15) and H (SOX30) (Table1). Individual members within a SOX subgroup have an overlapping function because of their similar biochemical properties [15]. On the other hand, there are many SOX factors from different groups show distinct biological functions despite their recognition of the same DNA consensus motif. Various SOX factors regulate genes selectively because of their differential affinity for particular flanking sequences next to consensus SOX sites as well as the dependency on their binding cofactors adjacent to the cognate sequence of a co-motif [16]. Additionally, homo- or heterodimerisation among SOX proteins, posttranslational modifications of SOX factors, or interaction with other cofactors showing cooperativity are the key deciding factors for a differential role of subgroup proteins in SOX family [15]. Significantly, having such molecular adaptability, the same SOX factors could play very dissimilar molecular and functional behaviours in diverse biological circumstances.
In this review, we discuss the current understanding of SOX family proteins in cancer research, subgroup-wise. Researchers have already shown the connection of SOX genes participating in a broader range of critical biological processes along with their involvement in a variety of diseases, primarily for genetic syndromes and cancer. We, here, particularly highlight the importance of several representative SOX proteins of a subgroup but describe all the subgroups of SOX family in cancer initiation and development.
Section snippets
SOX A subgroup (SRY)
Mammalian embryonic sex depends on the SRY gene of the SOX A family. The male phenotype of the embryo depends on the presence of at least one complete functional copy of SRY. The absence of SRY alters the pathways, and consequently, an XX genotype is responsible for the development of a female phenotype. The molecular analysis reveals the presence of SRY gene with a significant coding region in DNA. The result is the same for the DNA of blood and tissue. The presence of SRY determines the brain
SOX B1 & SOX B2 subgroups (SOX1, SOX2, SOX3, SOX14, and SOX21)
Although the SOX B subgroups comprise many SOX genes, arguably the most important of these is SOX2, a key regulator of many human cancers that is also the most studied gene in the SOXB group [24,25]. Along with glioblastoma multiform (GBM), various human cancers were reported to have significant SOX2 expression [26,27]. Remarkably, a subset of patients was identified with the help of SOX2 expression and other SOX markers generally found in stem cell. Regarding clinical relevance, the
SOX C subgroup (SOX4, SOX11, and SOX12)
In the biology of different mammalian brain tumours, the role of SOX C is also known [52,53]. In the GBM activity, SOX4 and SOX11 have opposing roles [[54], [55], [56]]. The upregulation of SOX 4 has been reported along with TGF-β in human samples [57]. The role of SOX4 in the signalling of GBM formation and progression is well established. The activation of canonical and non-canonical TGF-β signalling enhances the activity of GSCs tumour [[58], [59], [60]]. This activity is mediated with SOX4
SOX D subgroup (SOX5, SOX6, and SOX13)
Among SOX D subfamily genes, SOX13 is the most understood as a regulator in cancer initiation and development [78,79]. It is reported that microRNA-185 (miR-185) inhibits the tumour growth and enhance the resistance against the chemical [80]. The existing mechanism against this behaviour is mediated via SOX13 in non-small-cell carcinoma (NSCLC) [81,82]. Many studies revealed that miR-185 is highly down-regulated in NSCLC tumour tissues and cell lines [80]. On the contrary, the over-expression
SOX E (SOX8, SOX9, and SOX10)
SOX9 is one of the members of SOX E subgroup. Its role is associated with embryonic development, maintenance of pancreas, hair follicle, CNS, breast, and intestine [[89], [90], [91]]. SOX9, along with SOX10, is essential for gliogenesis in CNS [25,92,93]. The proliferation of glioma cell lines can be impaired by knocking down SOX9 [90], which leads to a suspended cell division in the G2/M phase of the cell cycle that leads to apoptosis in glioma cells [94]. Moreover, ectopic expression of SOX9
SOX F subgroups (SOX7, SOX17, and SOX18)
Breast cancer development and its progress depend on the silencing of epigenetic modulators as well as deletion of tumour suppressors. Several studies revealed that SOX7 is downregulated in different types of a cancer cell line, such as lung, colon, and prostate [[114], [115], [116], [117]]. Based on current findings, SRY-related HMG-box 7 (SOX7) mRNA and protein expression are less expressive in breast cancer cell lines for healthy mammalian tissues [[118], [119], [120], [121], [122], [123]].
SOX G subgroup (SOX15)
Cell proliferation, differentiation, and survival of tumours cells are governed by the WNT/B-CATENIN signalling pathways. It is considered as the key dysregulated pathways that depend on SOX15 for its modulation in different tumours types [149]. SOX15 regulates embryonic development and carcinogenesis [20,45,46]. SOX15 is regarded as a unique tumour suppressor in the esophagus, gastrointestinal parts, and pancreases, respectively, because of its potential role in modulating Wnt/b-catenin
SOX H subgroup (SOX30)
In the patient of lung cancer, SOX30, the lone member of SOX H subgroup was reported to prevent the metastasis of tumour cell by perturbing Wnt-signalling via transcriptional and posttranslational regulation of β-Catenin in lung cancer [23]. For the attenuating of β-catenin transcriptional activity, carboxyl-terminus of SOX30 is essential, whereas the amino-terminus is essential for its interaction with the β-catenin protein [19]. The enhancement of β-catenin attenuates the anti-metastatic role
Conclusion
Unprecedented progress in molecular research on SOX TFs over the last 25 years has demonstrated that SOX factors are exceptional, critical regulators of different cellular functions; especially cell fate decision. During embryogenesis, SOX factors are critical controllers that are maintaining neuronal stem cells and inducing lineage differentiation in the embryo development as well as in the adult stage. Furthermore, scientists also observed aberrant expression of these factors in malignant
Author contributions
PK and T.K.M. equally contributed to writing the manuscript.
Funding
Seed-fund from Lovely Professional University (2017–2019).
Acknowledgments
We sincerely thank Dr. Pranav Kumar Prabhakar for proofreading as well as for his valuable suggestions in the manuscript. We also heartily thank Prof. Ian Chambers from the centre for regenerative medicine, the UK for his all valuable contributions in the revision work. P.K. and T.K.M. gratefully acknowledges support by Lovely Professional University.
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