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Review
. 2020 Jul 29;5(1):135.
doi: 10.1038/s41392-020-00242-3.

Functional characterization of SOX2 as an anticancer target

Shizhen Zhang  1 , Xiufang Xiong  1 , Yi Sun  2
Affiliations
Review

Functional characterization of SOX2 as an anticancer target

Shizhen Zhang et al. Signal Transduct Target Ther. .

Abstract

SOX2 is a well-characterized pluripotent factor that is essential for stem cell self-renewal, reprogramming, and homeostasis. The cellular levels of SOX2 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and post-translation. In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression. SOX2 overexpression is associated with poor survival of cancer patients. Mechanistically, SOX2 promotes proliferation, survival, invasion/metastasis, cancer stemness, and drug resistance. SOX2 is, therefore, an attractive anticancer target. However, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2 as a transcription factor. In this review, we first briefly introduced SOX2 as a transcription factor, its domain structure, normal physiological functions, and its involvement in human cancers. We next discussed its role in embryonic development and stem cell-renewal. We then mainly focused on three aspects of SOX2: (a) the regulatory mechanisms of SOX2, including how SOX2 level is regulated, and how SOX2 cross-talks with multiple signaling pathways to control growth and survival; (b) the role of SOX2 in tumorigenesis and drug resistance; and (c) current drug discovery efforts on targeting SOX2, and the future perspectives to discover specific SOX2 inhibitors for effective cancer therapy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The SOX2 domain structures and the posttranslational modification sites. SOX2 protein consists of 317 amino acids with three functional domains: high mobility group (HMG) domain at the N-terminus, dimerization (DIM) domain at the center, and transactivation (TAD) domain at the C-terminus. SOX2 is subjected to modification at the posttranslational level by acetylation, phosphorylation, SUMOylation, ubiquitylation, methylation, O-Glycosylation, and PARPylation. Note that the PARPylation site has not been identified
Fig. 2
Fig. 2
The role of SOX2 in embryonic development, pluripotency, and homeostasis. SOX2 is initially expressed in pluripotent founder cells of blastocyst, and plays the key role in the embryonic development of three cell linages of ectoderm, endoderm, and mesoderm. SOX2 expression in adult stem and progenitor cells is essential for tissue homeostasis and regeneration. Dysregulation of SOX2 contributes to tumorigenesis
Fig. 3
Fig. 3
SOX2 is regulated at multiple levels. The SOX2 levels and activities are precisely regulated by a complicate network at the levels of transcription, post-transcription, and post-translation, as shown. At the transcriptional levels, SOX2 mRNA is either up- or downregulated by its enhancers, and other transcription activators or repressors. The post-transcriptional regulators are mainly the miRNAs and lncRNAs, that control the stability of SOX2 mRNA. The posttranslational regulators are a variety of enzymes that modify specific residues on SOX2 protein, leading to alterations in SOX2 activity, subcellular localization, and stability. MALAT1 metastasis-associated lung adenocarcinoma transcript 1, TUNA Tcl1 upstream neuron-associated lncRNA, DNMT DNA methyltransferase, OTUD7B OTU domain-containing protein 7B, OGT O-GlcNAc transferase
Fig. 4
Fig. 4
SOX2 cross-talks with various signaling pathways. SOX2 cross-talks with a variety of signaling pathways that regulate proliferation, survival, and tumorigenesis, including EGFR, SHH, HIPPO, WNT/β-Catenin, and TGF-β/Smads signaling pathways. In general, SOX2 positively or negatively regulates proliferative or antiproliferative signaling pathways, respectively, leading to enhanced proliferation, survival, and tumorigenesis
Fig. 5
Fig. 5
SOX2 regulates a variety of biological processes. SOX2 regulates various biological processes, leading to oncogenic consequence. In general, SOX2 represses cell cycle upon differentiation signals to maintain the stemness and accelerates cell-cycle progression upon growth signals for proliferation. SOX2 exerts an antiapoptotic effect to promote survival of cancer cells. SOX2 also triggers EMT process to enhance tumor invasion and metastasis. Finally, SOX2 induces cancer-specific autophagy to confer chemoresistance
Fig. 6
Fig. 6
Correlation of SOX2 levels with prognosis of cancer patients. In most human cancers, SOX2 overexpression or amplification is associated with poor survival of cancer patients. In certain types of cancers, such as gastric cancer, head and neck squamous cell carcinoma, and LSCC, higher SOX2 levels are associated with a better patient survival. SCLC small cell lung cancer, LSCC lung squamous cell carcinoma
Fig. 7
Fig. 7
SOX2-targeting approaches. Currently, the approaches undertaken to target SOX2 includes: (1) to alter the endogenous SOX2 gene expression by direct gene targeting using the zinc-finger (ZF)-based artificial transcription factor (ATF); (2) to generate the peptide aptamer for SOX2 targeting; (3) to target the SOX2-DNA binding, thus inhibiting SOX2 transcriptional activity; (4) to target SOX2 via inducing immune responses; (4) to use small molecules inhibitors of signaling pathways that affect SOX2, thus indirectly inhibiting SOX2; (6) to target protein ubiquitylation and degradation to specifically shut down SOX2 expression; (7) to develop the PROteolysis Targeting Chimera (PROTAC) method to directly degrade SOX2
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References

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