STAT3 Inhibition Attenuates MYC Expression by Modulating Co-Activator Recruitment and Suppresses Medulloblastoma Tumor Growth by Augmenting Cisplatin Efficacy In Vivo.

MB is a common childhood malignancy of the central nervous system, with significant morbidity and mortality. Among the four molecular subgroups, MYC-amplified Group 3 MB is the most aggressive type and has the worst prognosis due to therapy resistance. The present study aimed to investigate the role of activated STAT3 in promoting MB pathogenesis and chemoresistance via inducing the cancer hallmark MYC oncogene.

Elevating SOX2 Downregulates MYC through a SOX2:MYC Signaling Axis and Induces a Slowly Cycling Proliferative State in Human Tumor Cells.

Slowly cycling/infrequently proliferating tumor cells present a clinical challenge due to their ability to evade treatment. Previous studies established that high levels of SOX2 in both fetal and tumor cells restrict cell proliferation and induce a slowly cycling state. However, the mechanisms through which elevated SOX2 levels inhibit tumor cell proliferation have not been identified.

Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth.

Background: Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent.

Elevating SOX2 in prostate tumor cells upregulates expression of neuroendocrine genes, but does not reduce the inhibitory effects of enzalutamide.

Prostate cancer (PCa) is one of the leading causes of cancer deaths in men. In this cancer, the stem cell transcription factor SOX2 increases during tumor progression, especially as the cancer progresses to the highly aggressive neuroendocrine-like phenotype. Other studies have shown that knockdown of RB1 and TP53 increases the expression of neuroendocrine markers, decreases the sensitivity to enzalutamide, and increases the expression of SOX2.

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro.

Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly malignancies. Recently, the deubiquitinating protease USP9X has been shown to behave as an oncogene in a number of neoplasms, including those of breast, brain, colon, esophagus and lung, as well as KRAS wild-type PDAC. However, other studies suggest that USP9X may function as a tumor-suppressor in a murine PDAC model when USP9X expression is depleted during early pancreatic development.

The SOX2-interactome in brain cancer cells identifies the requirement of MSI2 and USP9X for the growth of brain tumor cells.

Medulloblastomas and glioblastomas, the most common primary brain tumors in children and adults, respectively, are extremely difficult to treat. Efforts to identify novel proteins essential for the growth of these tumors may help to further our understanding of the biology of these tumors, as well as, identify targets for future therapies. The recent identification of multiple transcription factor-centric protein interaction landscapes in embryonic stem cells has identified numerous understudied proteins that are essential for the self-renewal of these stem cells.

Elevating SOX2 levels deleteriously affects the growth of medulloblastoma and glioblastoma cells.

Medulloblastomas and glioblastomas are devastating tumors that respond poorly to treatment. These tumors have been shown to express SOX2 and overexpression of SOX2 has been correlated with poor prognosis. Although knockdown of SOX2 impairs the growth and tumorigenicity of brain tumor cells, it was unclear how elevating SOX2 levels would affect their fate.

Structural basis of Ets1 cooperative binding to palindromic sequences on stromelysin-1 promoter DNA.

Ets1 is a member of the Ets family of transcription factors. Ets1 is autoinhibited and its activation requires heterodimerization with a partner protein or DNA-mediated homodimerization for cooperative DNA binding. In the latter case, Ets1 molecules bind to palindromic sequences in which two Ets-binding sites (EBS) are separated by four base pairs, for example in the promoters of stromelysin-1 and p53.

Crystal structure of mouse Elf3 C-terminal DNA-binding domain in complex with type II TGF-beta receptor promoter DNA.

The Ets family of transcription factors is composed of more than 30 members. One of its members, Elf3, is expressed in virtually all epithelial cells as well as in many tumors, including breast tumors. Several studies observed that the promoter of the type II TGF-beta receptor gene (TbetaR-II) is strongly stimulated by Elf3 via two adjacent Elf3 binding sites, the A-site and the B-site.

Comparison of ras-responsive gene enhancers in pancreatic tumor cells that express either wild-type or mutant K-ras.

There is a pressing need for new therapies to treat pancreatic cancer. In principle, this could be achieved by taking advantage of signaling pathways that are active in tumor, but not normal, cells. The work described in this study set out to determine whether the activities of three enhancers, which have been reported to be highly responsive to activated ras, differ in pancreatic tumor cells that express wild-type versus constitutively active mutant forms of K-ras.

Elevating the levels of Sox2 in embryonal carcinoma cells and embryonic stem cells inhibits the expression of Sox2:Oct-3/4 target genes.

Recent studies have identified large sets of genes in embryonic stem and embryonal carcinoma cells that are associated with the transcription factors Sox2 and Oct-3/4. Other studies have shown that Sox2 and Oct-3/4 work together cooperatively to stimulate the transcription of their own genes as well as a network of genes required for embryogenesis. Moreover, small changes in the levels of Sox2:Oct-3/4 target genes alter the fate of stem cells.

Different domains of the transcription factor ELF3 are required in a promoter-specific manner and multiple domains control its binding to DNA.

Elf3 is an epithelially restricted member of the ETS transcription factor family, which is involved in a wide range of normal cellular processes. Elf3 is also aberrantly expressed in several cancers, including breast cancer. To better understand the molecular mechanisms by which Elf3 regulates these processes, we created a large series of Elf3 mutant proteins with specific domains deleted or targeted by point mutations.

Differential activity of the FGF-4 enhancer in F9 and P19 embryonal carcinoma cells.

Transcription factors Oct-3/4 and Sox2 behave as global regulators during mammalian embryogenesis. They work together by binding co-operatively to closely spaced HMG and POU motifs (HMG/POU cassettes). Recently, it was suggested that a critical Sox2:Oct-3/4 target gene, FGF-4, is expressed at lower levels in P19 than in F9 embryonal carcinoma (EC) cells, due to lower levels of Sox2 in P19 than in F9 cells.

Transcriptional regulation of the murine Elf3 gene in embryonal carcinoma cells and their differentiated counterparts: requirement for a novel upstream regulatory region.

The transcription factor Elf3, which is one of over 25 Ets family members, is expressed in a wide variety of carcinomas and has been shown to promote the transcription of many genes implicated in cancer. To understand how the Elf3 gene is regulated at the transcriptional level, we probed its 5'-flanking region, and we report here the identification of both proximal and distal regions that regulate murine Elf3 promoter activity. In addition to mapping the transcription start site of the Elf3 gene, the work described in this study identifies four cis-regulatory elements in the proximal promoter region of the gene.

Unique and selective effects of five Ets family members, Elf3, Ets1, Ets2, PEA3, and PU.1, on the promoter of the type II transforming growth factor-beta receptor gene.

Previous studies have shown that the promoter of the type II TGF-beta receptor gene (TbetaR-II) is strongly stimulated by Elf3, a member of the Ets transcription factor family. The TbetaR-II gene behaves as a tumor suppressor and it is expressed in nearly all cell types, whereas Elf3 is expressed primarily in epithelial cells. Hence, the TbetaR-II gene is likely to be regulated by other Ets proteins in nonepithelial cells.

Stimulation of the murine type II transforming growth factor-beta receptor promoter by the transcription factor Egr-1.

Previous studies have demonstrated that differentiation of murine embryonal carcinoma (EC) cells leads to the appearance of high affinity receptors for transforming growth factor-beta (TGF-beta). Subsequently, it was demonstrated that differentiation of F9 EC cells leads to increases in the transcription of the type II TGF-beta-receptor gene (TbetaR-II) and leads to significant increases in the steady-state levels of TbetaR-II mRNA. Analysis of the human TbetaR-II promoter in F9-differentiated cells identified several cis-regulatory elements that influence the activity of the promoter, including a CRE/ATF site and a CCAAT box motif.

Activation of the murine type II transforming growth factor-beta receptor gene: up-regulation and function of the transcription factor Elf-3/Ert/Esx/Ese-1.

Previous studies demonstrated that differentiation of mouse embryonal carcinoma cells leads to transcriptional up-regulation of the mouse type II transforming growth factor-beta receptor (mTbetaR-II) gene. To elucidate the molecular mechanisms regulating transcription of this gene, we isolated the 5'-flanking region of the mTbetaR-II gene and characterized its expression in F9-differentiated cells. Analysis of mTbetaR-II promoter/reporter gene constructs demonstrates that two conserved Ets-binding sites play an important role in the activity of the mTbetaR-II promoter.