SOX2 in cancer stemness: tumor malignancy and therapeutic potentials

Abstract

Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity

“…Figure 6C shows that nandrolone treatment of HepG2 under 3D culturing condition resulted in decrease of the spheroid area which was significant after 7 days culturing. Most notably the expression of Sox2, a transcription factor driving cancer stemness 29 , increased significantly already after 3 days of spheroid culturing ( Fig. 6D) Housekeeping gene expression was not substantially changed by ND treatment neither in 2D nor in 3D cultures as compared with vehicle-treated samples ( Supplementary Fig.…”

Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis

“…Parsing the RNA-Seq data, we identified pluripotency-associated transcription factors-Sox2 and Nanog-as significantly overexpressed in "KAC-P" cells (Table S2) and confirmed high Sox2 expression and open promoter in "KAC" cells compared to control "KC" (Figure 5F,G). Both transcription factors are aberrantly expressed in multiple cancers, including PDAC [12][13][14] and believed to mark cancer stem cells and promote EMT [15], suggesting that transcription factors implicated in stem cell identity might also play a role in development of PDAC in "KAC" mice. Representative plots from GSEA analysis of differentially expressed genes (2-fold change) identified from RNA-seq on "KC" and "KPC-P" cells revealed positive enrichment in hallmark of EMT and Myc target genes and negative enrichment in Kras dependency gene signature and hallmark P53 pathway.…”

The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes

“…The transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells [1][2][3][4], is causally related to tumor initiation, aggressiveness, and metastasis likely due to its ability to induce and maintain the stemness of cancer stem cells (CSC) [5,6]. Given that a key mechanism of drug resistance relates to the incapacity of most standard therapeutics to eradicate the minor subpopulation of CSC with selfrenewal and seeding capacity, SOX2 has been suggested as an attractive anti-cancer target to prevent CSC-mediated clinical relapse [7,8].…”