Functional characterization of SOX2 as an anticancer target

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 posttranslation. 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.

Nectin-4 and p95-ErbB2 cooperatively regulate Hippo signaling-dependent SOX2 gene expression, enhancing anchorage-independent T47D cell proliferation

“…YAP is a transcriptional co-activator that enhances cell proliferation and inhibits cell death by its association with the TEAD family of transcription factors 50 . YAP enhances or decreases the SOX2 gene expression depending on cell types 49 , 51 – 54 , and we showed here that YAP inhibited the SOX2 gene expression in T47D cells. Thus, nectin-4 and p95-ErbB2 activated the MST1/2-LATS1/2 signaling to suppress the inhibitory role of YAP in the PI3K-AKT signaling-mediated SOX2 gene expression, eventually enhancing T47D cell proliferation through upregulated SOX2 in a serum-free suspension culture.…”

“…SOX2 is an essential transcription factor for maintaining self-renewal of undifferentiated embryonic and tissue stem cells, thus regulating embryogenesis and normal development 45 , 46 . SOX2 is also expressed in many types of cancer cells and regulates their proliferation, survival, differentiation, and tolerance to anti-cancer drugs 45 – 49 . The SOX2 gene expression is induced by many signaling pathways including the PI3K-AKT signaling 45 – 49 .…”

“…SOX2 is also expressed in many types of cancer cells and regulates their proliferation, survival, differentiation, and tolerance to anti-cancer drugs 45 – 49 . The SOX2 gene expression is induced by many signaling pathways including the PI3K-AKT signaling 45 – 49 . Detailed studies revealed here that nectin-4 and any one of p95-ErbB2, ErbB2, or ErbB2∆Ex16 cooperatively activated the PI3K-AKT signaling to similar extents 33 , but that only the combination of nectin-4 and p95-ErbB2, but not that of nectin-4 and either ErbB2 or ErbB2∆Ex16, cooperatively activated the Hippo signaling to regulate the SOX2 gene expression.…”

The adaptive transition of glioblastoma stem cells and its implications on treatments

“…A recent study summarized the efficacy of strategy that by targeting SOX2 on stem-like cells can inhibit tumor progression. 189 Clinical trials targeting GSCs Apart from traditional treatments of GBM, several clinical trials proposed a novel strategy in recent years. All information about clinical trials is obtained from public clinical trial databases (https://clinicaltrials.gov/).…”

“…A recent study summarized the efficacy of strategy that by targeting SOX2 on stem-like cells can inhibit tumor progression. 189 …”