Protein & Cell | 2019
Targeting oncogenic SOX2 in human cancer cells: therapeutic application
Abstract
Sry-related high-mobility box 2 (SOX2) is a critical transcription factor that plays an important role in various phases of embryonic development and maintenance of undifferentiated embryonic stem cells (ESCs) (Feng and Wen, 2015). SOX2, as one of the Yamanaka factors, is involved in the conversion of mouse embryonic fibroblast cells (MEFs) into induced pluripotent stem cells (iPSCs) (Takahashi and Yamanaka, 2006). Recently, SOX2 amplification, usually couples with aberrantly increased expression, were found in various human cancers, including breast, lung, esophagus, colon, prostate, ovarian among the others (Novak et al., 2019). SOX2 overexpression promotes cancer progression by accelerating cell proliferation, colony formation, migration, invasion, and sphere formation. Furthermore, SOX2 is causally related to the development of the resistance of cancer cells to chemotherapy, radiotherapy and targeted therapy in different types of human cancers, likely due to its ability to maintain the stemness of cancer stem cells (CSCs), which are defined as a subpopulation within tumor cells being equipped with stem cell-like properties that survives the treatment and initiates tumor progression (Novak et al., 2019). Thus, SOX2 has been validated as an attractive anticancer target (Huser et al., 2018). Given its biological significance, SOX2 levels are precisely controlled by a complicated network of transcriptional, post-transcriptional, and post-translational regulators. At the transcriptional level, the two isoforms of E2f transcription factor 3 (E2f3), E2f3a and E2f3b, regulate SOX2 expression in a reciprocal way (Wuebben and Rizzino, 2017). The cyclin-dependent kinase inhibitor p21 directly binds to the SOX2 enhancer and negatively regulates SOX2 transcription (Wuebben and Rizzino, 2017), whereas transforming growth factor-β (TGFβ) or sirtuin 1 (SIRT1) induces SOX2 via SOX4 (Wuebben and Rizzino, 2017), or via chromatinbased epigenetic modification (Liu et al., 2016), respectively. More recently, a homeobox-containing transcription factor, muscle segment homeobox-2 (MSX2) was shown to destabilize the pluripotency circuitry by direct binding to the SOX2 promoter to repress SOX2 transcription (Wu et al., 2015). At the post-transcriptional level, SOX2 is subjected to regulation by several microRNAs and long non-coding RNAs in cancer cells (Wuebben and Rizzino, 2017). Finally, at the post-translational level, SOX2 protein is modulated by phosphorylation, sumoylation, methylation, acetylation and ubiquitylation. Phosphorylation of SOX2 at S249, S250 and S251 residues affects its stability (Wuebben and Rizzino, 2017), whereas sumoylation of SOX2 impairs its DNAbinding property and thus inhibiting its transcription activity (Wuebben and Rizzino, 2017). Notably, SOX2 is subjected to ubiquitylation by ubiquitin-conjugating enzyme UBE2S and CUL4A E3 ligase, respectively (Cui et al., 2018; Wuebben and Rizzino, 2017). The methylation of SOX2 is required for ubiquitylation and proteolysis mediated by HECT domain-containing WWP2 E3 ligase (Wuebben and Rizzino, 2017), and the CRL4 ubiquitin ligase complex (Zhang et al., 2019). Although SOX2 is highly relevant to cancer initiation, progression and development of drug resistance, directly targeting SOX2 has been proved to be difficult, since SOX2 is an “undrugable” transcription factor. The multiple preclinical studies have shown that SOX2 knockdown mediated by siRNAs, shRNAs or miRNAs dramatically suppresses proliferation and invasion of cancer cells in both in vitro cell culture and in vivo xenograft tumor models (Huser et al., 2018). These studies validate SOX2 as a promising target, but offer little therapeutic value due to huge challenge in efficacy and delivery. On the other hand, zinc-finger (ZF)based artificial transcription factors (ATFs), which bind