DNMT3B has oncogenic activity but evidence suggests that it does not promote CIMP nor cooperate with activated BRAFV600E in human intestinal cancer.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE126434 | GEO | 2020/02/18
REPOSITORIES: GEO
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Project description:Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG Island Methylator Phenotype (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells are thought to respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by multiple approaches. By analysis of human TCGA data, we confirmed that expression of DNMT3B is frequently upregulated in CRC and this is often linked to amplification of the DNMT3B gene. In vitro, we found that ectopic expression of DNMT3B antagonizes BRAFV600E-induced proliferation arrest and inflammatory gene expression, two hallmarks of the tumor suppressive senescence program triggered by oncogenes in primary cells. Moreover, DNMT3B over expression decreased survival in a mouse model of BRAFV600E-induced intestinal cancer. However, in primary human cells in vitro, activated BRAFV600E repressed expression of DNMT3B and failed to induce a CIMP phenotype. Finally, a closer analysis of human TCGA data revealed that BRAFV600E mutations and CIMP are both linked to a low expression of DNMT3B. We conclude that while both BRAFV600E and DNMT3B both harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumour promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.
2020-02-18 | GSE126433 | GEO
Project description:Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG Island Methylator Phenotype (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells are thought to respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by multiple approaches. By analysis of human TCGA data, we confirmed that expression of DNMT3B is frequently upregulated in CRC and this is often linked to amplification of the DNMT3B gene. In vitro, we found that ectopic expression of DNMT3B antagonizes BRAFV600E-induced proliferation arrest and inflammatory gene expression, two hallmarks of the tumor suppressive senescence program triggered by oncogenes in primary cells. Moreover, DNMT3B over expression decreased survival in a mouse model of BRAFV600E-induced intestinal cancer. However, in primary human cells in vitro, activated BRAFV600E repressed expression of DNMT3B and failed to induce a CIMP phenotype. Finally, a closer analysis of human TCGA data revealed that BRAFV600E mutations and CIMP are both linked to a low expression of DNMT3B. We conclude that while both BRAFV600E and DNMT3B both harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumour promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.
2020-02-18 | GSE126311 | GEO
Project description:Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG island methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.
| S-EPMC7000804 | biostudies-literature
Project description:DNMT3B has oncogenic activity but evidence suggests that it does not promote CIMP nor cooperate with activated BRAFV600E in human intestinal cancer.
| PRJNA521880 | ENA
Project description:DNMT3B has oncogenic activity but evidence suggests that it does not promote CIMP nor cooperate with activated BRAFV600E in human intestinal cancer. (WGBS)
| PRJNA521885 | ENA
Project description:DNMT3B has oncogenic activity but evidence suggests that it does not promote CIMP nor cooperate with activated BRAFV600E in human intestinal cancer. (RNA-Seq)
| PRJNA521531 | ENA
Project description:The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of RasV12-induced cell tumours in the brain. Notably, effects were restricted to two populations of Repo-positive glial cells: an invasive population, characterized by JNK-dependent elevation of Mmp1 expression, and a hyperproliferative population lacking elevated JNK signalling. JNK activation was not triggered by reactive immune cell signalling, implicating the involvement of an intrinsic stress response. The ability to promote dissemination of RasV12-induced tumours was shared by a subset of actin regulators, including, most prominently, Chicadee/Profilin, which directly interacts with Pico, and, Mal, a cofactor for serum response factor that responds to changes in G:F actin dynamics. Suppression of Mal activity partially abrogated the ability of pico to promote invasion of RasV12 tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/RasV12 overexpression. Taken together, our findings indicate that MRL proteins cooperate with oncogenic Ras to promote formation of glial tumours, and that, in this context, Mal/serum response factor activation is rate-limiting for tumour dissemination.
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Project description:Regulatory T cells (Treg) are critical mediators of immunosuppression in established tumors, although little is known about their role in restraining immunosurveillance during tumorigenesis. Here, we employ an inducible autochthonous model of melanoma to investigate the earliest Treg and CD8 effector T-cell responses during oncogene-driven tumorigenesis. Induction of oncogenic BRAFV600E and loss of Pten in melanocytes led to localized accumulation of FoxP3+ Tregs, but not CD8 T cells, within 1 week of detectable increases in melanocyte differentiation antigen expression. Melanoma tumorigenesis elicited early expansion of shared tumor/self-antigen-specific, thymically derived Tregs in draining lymph nodes, and induced their subsequent recruitment to sites of tumorigenesis in the skin. Lymph node egress of tumor-activated Tregs was required for their C-C chemokine receptor 4 (Ccr4)-dependent homing to nascent tumor sites. Notably, BRAFV600E signaling controlled expression of Ccr4-cognate chemokines and governed recruitment of Tregs to tumor-induced skin sites. BRAFV600E expression alone in melanocytes resulted in nevus formation and associated Treg recruitment, indicating that BRAFV600E signaling is sufficient to recruit Tregs. Treg depletion liberated immunosurveillance, evidenced by CD8 T-cell responses against the tumor/self-antigen gp100, which was concurrent with the formation of microscopic neoplasia. These studies establish a novel role for BRAFV600E as a tumor cell-intrinsic mediator of immune evasion and underscore the critical early role of Treg-mediated suppression during autochthonous tumorigenesis.Significance: This work provides new insights into the mechanisms by which oncogenic pathways impact immune regulation in the nascent tumor microenvironment. Cancer Res; 78(17); 5038-49. ©2018 AACR.
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Project description:Balancing cellular demise and survival constitutes a key feature of resilience mechanisms that underlie the control of epithelial tissue damage. These resilience mechanisms often limit the burden of adaptive cellular stress responses to internal or external threats. We recently identified Diedel, a secreted protein/cytokine, as a potent antagonist of apoptosis-induced regulated cell death in the Drosophila intestinal midgut epithelium during aging. Here, we show that Diedel is a ligand for RGD-binding Integrins and is thus required for maintaining midgut epithelial cell attachment to the extracellular matrix (ECM)-derived basement membrane. Exploiting this function of Diedel, we uncovered a resilience mechanism of epithelial tissues, mediated by Integrin-ECM interactions, which shapes cell death spreading through the regulation of cell detachment and thus cell survival. Moreover, we found that resilient epithelial cells, enriched for Diedel-Integrin-ECM interactions, are characterized by membrane association of Catalase, thus preserving extracellular reactive oxygen species (ROS) balance to maintain epithelial integrity. Intracellular Catalase can relocalize to the extracellular membrane to limit cell death spreading and repair Integrin-ECM interactions induced by the amplification of extracellular ROS, which is a critical adaptive stress response. Membrane-associated Catalase, synergized with Integrin-ECM interactions, likely constitutes a resilience mechanism that helps balance cellular demise and survival within epithelial tissues.
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