Section 3.1: Major transcription factors in CSCs (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 3.1: Major transcription factors in CSCs
Generally, stem cells have at least two common characteristics: the ability to self-renew and the potential to differentiate into one or more specialized cell types. Somatic cells can be reprogrammed to become induced pluripotent stem cells by transient ectopic overexpression of the transcription factors Oct4, Sox2, Nanog, KLF4, and MYC. In addition, there are some similarities between CSCs and ES cells. It is reasonable that some embryonic transcription factors can be re-expressed or reactivated in CSCs. Therefore, these transcription factors play a very important role in the regulation of CSC growth.
Oct4, a homeodomain transcription factor of the Pit-Oct-Unc family, is recognized as one of the most important transcription factors. Recently, Oct4 has emerged as a master regulator that controls pluripotency, self-renewal, and maintenance of stem cells. Some studies have reported that Oct4 is highly expressed in CSCs. High expression of Oct4 is positively correlated with glioma grades and promotes self-renewal, chemoresistance, and tumorigenicity of HCC stem cells. High expression of Oct4 is also observed in breast CSC-like cells (CD44+/CD24-). Cisplatin, etoposide, adriamycin, and paclitaxel gamma-irradiation upregulate the expression of Oct4 in lung cancer cells, and CD133+ cells are more resistant to drug treatments than CD133- cells. Data also show that Oct4 expression is associated with poor clinical outcome in hormone receptor-positive breast cancer. Knockdown of Oct4 also reduces the stemness of germ cell tumors. Hence, these studies have proven that Oct4 is a pluripotent factor in CSCs.
Sox2 belongs to the family of high-mobility group transcription factors and plays a significant function in the early development and maintenance of undifferentiated ESCs. It is also one of the key transcription factors in CSCs. Rodriguez-Pinilla et al. found that increased expression of Sox2 in basal-like breast cancer may help to characterize poorly differentiated/stem cell phenotypes. Hagerstrand et al. also found that a high level of Sox2 can induce xenograft glioma. Further studies showed that knockout of Sox2 inhibits glioblastoma cell proliferation and tumorigenicity, which suggests that Sox2 is the basis for maintaining the self-renewal ability of tumor-initiating cells (TICs). Sox2 also maintains the self-renewal of TICs in osteosarcomas, and downregulation of Sox2 drastically decreases its transformative characteristics and tumorigenesis ability in vitro. Furthermore, osteosarcoma cells that lose Sox2 cannot form osteospheres and differentiate into mature osteoblasts any longer. Sox2 is found in invasive cutaneous squamous cell carcinoma (SCC) and promotes the metastasis of cancer cells. These studies suggest that Sox2 promotes self-renewal and tumorigenesis and inhibits differentiation in CSCs.
Nanog, a differentiated homeobox (HOX) domain protein that was first discovered in ESCs, has typical self-renewal and multipotent transcriptional regulatory functions. Although Nanog is silenced in normal somatic cells, abnormal expression has been reported in human cancers, such as breast cancer, cervical cancer, brain cancer, colon cancer, head and neck cancer, lung cancer, and gastric cancer. Compared to levels in benign tissues, Nanog messenger RNA (mRNA) is elevated in malignant tumors. In a number of patients with colorectal cancer (n = 175), high Nanog protein is associated with lymph node positivity and Dukes grade. Similarly, overexpression of Nanog in colorectal CSCs promotes colony formation and tumorigenicity in vivo. In addition, gastric cancer patients with high Nanog levels have a lower 5-year survival rate. The expression level of Nanog is increased in HCC cell lines and primary tumors and is associated with advanced diseases (tumor node metastasis (TNM) stage III/IV). Through the study of prostatic cell lines, xenografts and primary tumors, it was found that Nanog short hairpin RNA inhibits the formation of primary prostate cancer cells (PCA) spheres, clonal growth, and tumorigenesis. In 43 cases of pancreatic cancer tissue microarray analysis, Kaplan-Meier analysis showed that high expression of Nanog (and Oct4) predicted worse prognosis and was negatively correlated with patient survival. These studies indicate that Nanog plays an important role in regulating the self-renewal and proliferation of CSCs.
KLF4 is expressed in many tissues and plays an important role in many different physiological processes. As a bifunctional transcription factor, KLF4 activates or inhibits transcription according to different target genes and utilizing different mechanisms. KLF4 can play an oncogenic or anticancer role, depending on the type of cancer involved. For example, KLF4 is an anticancer factor in the intestinal epithelium and gastric epithelium. The expression of KLF4 is downregulated with hypermethylation and loss of heterozygosity in colorectal CSCs and gastric CSCs. Downregulation of KLF4 is also found in other cancers, such as non-small-cell lung carcinoma, liver cancer, leukemia, anaplastic meningioma, bladder cancer, and esophageal cancer. Although these data clearly demonstrate that KLF4 plays an anticancer role in those cancers, KLF4 may also be an oncogene, which was demonstrated for the first time in nearly a decade. Overexpression of KLF4 in transformed rat renal epithelial cells induces tumorigenesis of laryngeal SCC. In addition, depletion of KLF4 inhibits melanoma xenograft growth in vivo. High expression of KLF4, an oncogene in human breast CSCs, is correlated with an aggressive phenotype in canine mammary tumors. These studies suggest that KLF4 has different functions in different CSCs.
MYC has three family members (C-Myc, N-Myc, and L-Myc, which are encoded by the proto-oncogene family and are essential transcription factors in the DNA-binding proteins of the basic helix-loop-helix (bHLH) superfamily). MYC regulates a large number of protein-coding and noncoding genes and coordinates various biological processes in stem cells, such as cell metabolism, self-renewal, differentiation, and growth. Although the MYC gene is one of the most commonly activated oncogenes that is involved in the pathogenesis of human cancer, overexpression of MYC alone is surprisingly unable to induce the transformation of normal cells into tumor cells. The overexpression of MYC in normal human cells may be ineffective or highly destructive, resulting in stagnation of proliferation, aging, or apoptosis. MYC is usually deregulated in human cancers, plays an important role in maintaining the number of invasive CSCs, and is also one of the most effective oncogenes for detecting the cell transformation phenotype in vitro and in vivo. Previous studies have shown that deletion of the tumor suppressor gene p53 and MYC synergizes to induce hepatocyte proliferation and tumorigenesis. In addition to p53 deletion, overexpression of Bcl-2 and Bmi-1 and loss of p19ARF also assist MYC in regulating the survival and proliferation of CSCs. The expression of the three members of the MYC family is different in different tumors, such as C-MYC in leukemia and tongue SCC stem cells and N-MYC in small-cell lung cancer, prostate cancer, neuroblastoma, and medulloblastoma. L-MYC is expressed in hematopoietic malignancies. In addition, inactivation of MYC results in HCC stem cells differentiating into hepatocytes and biliary duct cells to form bile duct structures, which might be associated with the loss of the tumor marker alpha-fetoprotein and increased expression of cytokeratin 8, hepatocyte markers, carcinoembryonic antigen, and the liver stem cell marker cytokeratin 19. Studies have also shown that MYC is highly expressed in glioblastoma multiforme stem cells and induces cell proliferation and invasion and inhibits apoptosis. Increased copy number of the MYC gene in human and mouse prostate CSCs has also been found. These studies indicate that MYC induces tumorigenesis with the help of other factors.
