Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice

Abstract

Ovarian cancer (OC) is one of the deadliest cancers among women contributing to high risk of mortality, mainly owing to delayed detection. There is no specific biomarker for its detection in early stages. However, recent findings show that over-expression of specificity protein 1 (Sp1) is involved in many OC cases. The ubiquitous transcription of Sp1 apparently mediates the maintenance of normal and cancerous biological processes such as cell growth, differentiation, angiogenesis, apoptosis, cellular reprogramming and tumorigenesis. Sp1 exerts its effects on cellular genes containing putative GC-rich Sp1-binding site in their promoters. A better understanding of the mechanisms underlying Sp1 transcription factor (TF) regulation and functions in OC tumorigenesis could help identify novel prognostic markers, to target cancer stem cells (CSCs) by following cellular reprogramming and enable the development of novel therapies for future generations. In this review, we address the structure, function, and biology of Sp1 in normal and cancer cells, underpinning the involvement of Sp1 in OC tumorigenesis. In addition, we have highlighted the influence of Sp1 TF in cellular reprogramming of iPSCs and how it plays a role in controlling CSCs. This review highlights the drugs targeting Sp1 and their action on cancer cells. In conclusion, we predict that research in this direction will be highly beneficial for OC treatment, and chemotherapeutic drugs targeting Sp1 will emerge as a promising therapy for OC.

Keywords: Sp1; cellular reprogramming; ovarian cancer; therapeutics approach; transcription factor.

Figure 1

The Co-crystallized Structure of specificity protein 1 (Sp1). The Sp1 protein is 785 amino acids long with a molecular weight of 81 kDa. The figure depicts the co-crystallized structure of Sp1, where the protein has three highly homologous C2H2 –type zinc finger motif-rich regions. This region is responsible for the binding to GC-rich DNA motifs (such as 5′-G/T-GGGCGG-G/A-G/A-C/T-3′ or 5′-G/T-G/A-GGCG-G/T-G/A-G/A-C/T-3′) and for the regulation of gene transcription of a large number of genes involved in various processes such as response to DNA damage, chromatin remodeling, cell growth, apoptosis, differentiation, and immune responses. The transcriptional activity of Sp1 can be modulated by several post-translational modifications including phosphorylation, acetylation, ubiquitylation, sumoylation, and glycosylation. The phosphorylation sites such as Ser59, Ser101, Ser131, Thr278, Thr335, and Thr453, were indicated in the figure. (Figures have been created with BioRender.io https://biorender.com/).

Figure 2

Role of Sp1 in the cell cycle. Improper functioning of the cell cycle and its checkpoints are generally a key factor for cancer cell growth. Some major interactions between the activity of transcription factor Sp1 and different components of the cell cycle phases, and its coordinating regulators have been depicted in this figure. In the G1 phase of the cell cycle, an elevated level of nuclear Sp1 augments the proliferation of Sp1-responsive genes such as ODC and cyclin D1. In M-phase of cell cycle, Sp1 TF acts as a mitotic substrate of CDK1/cyclin B1. In G2 phase of cell cycle Sp1 undergoes phosphorylation due to cyclin A-CDK complexes. In the transition periods from G1/S phase, Sp1 stimulates cyclin D/Cdk4, cyclin E/Cdk2, E2f–1, and c–myc genes. These interfaces often result into an abnormal cell cycle progression and possibly into cancer cell growth and progression. (Figures have been created with BioRender.io https://biorender.com/).

Figure 3

Sp1 mediated tumorigenesis in ovarian cancer (OC). Evasion in the Sp1 transcriptional activities at various levels has been found as a cause for tumorigenesis in OC cells. In OC cells, the transcription activity of Sp1 can be enhanced by various oncogenes like Ras, Src, and Raf especially through MAP3K, PI3K/AKT, and JNK1 pathway. In addition, Sp1 affects the tumorigenesis by activating the pro–oncogenes such as HBXIP, CLDN4, and MDM2, resulting in the migration of OC cells. Furthermore, Sp1 is seen to up-regulate VEGF and survivin genes, leading to angiogenesis and anti–apoptosis in the OC cells (Figures have been created with BioRender.io https://biorender.com/).

Figure 4

Potential role of Sp1 transcription factor in cellular reprogramming. Sp1 is one of the most important transcription factors that are associated with the major reprogramming factors Sox2, c-Myc, and Oct4, that are used for iPSC induction. Sp1 TF is an analog for Klf4 TF, thus Sp1 do play a major role in reprogramming process of cancer stem cells. Sp1 was also considered as a vital component involved in the conversion of somatic cells into pluripotent cells making it a target to increase the efficiency of reprogramming.