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MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3

ABSTRACT: The transcription factor MYB proto-oncogene like 2 (MYBL2) plays a critical role in the regulation of gene expression and tumorigenesis. However, the biological function of MYBL2 in bladder cancer (BLCA) remains to be elucidated. Here, we first revealed that MYBL2 was elevated in BLCA tissues and was significantly correlated with clinicopathological parameters and cancer-specific survival of BLCA patients. Phenotypic assays showed that MYBL2 deficiency suppressed the proliferation and migration of BLCA cells in vitro and in vivo, whereas overexpression of MYBL2 contributed to the opposite phenotype. Mechanistically, MYBL2 could bind to the promoter of its downstream target gene cell division cycle-associated protein 3 (CDCA3) and transactivate it, which in turn promoted the malignant phenotype of BLCA cells. Further investigations revealed that MYBL2 interacted with forkhead box M1 (FOXM1) to co-regulate the transcription of CDCA3. In addition, MYBL2 and CDCA3 may activate the Wnt/β-catenin signaling by inhibiting the suppressor dickkopf-1 (DKK1), thereby regulating the malignant phenotype of BLCA cells. In conclusion, the current study has identified MYBL2 as an oncogene in BLCA. MYBL2 can accelerate the proliferation and metastasis of BLCA through the transactivation of CDCA3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201875 | GEO | 2022/05/02

REPOSITORIES: GEO

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MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3

Project description:The transcription factor MYB proto-oncogene like 2 (MYBL2) plays a critical role in the regulation of gene expression and tumorigenesis. However, the biological function of MYBL2 in bladder cancer (BLCA) remains to be elucidated. Here, we first revealed that MYBL2 was elevated in BLCA tissues and was significantly correlated with clinicopathological parameters and cancer-specific survival of BLCA patients. Phenotypic assays showed that MYBL2 deficiency suppressed the proliferation and migration of BLCA cells in vitro and in vivo, whereas overexpression of MYBL2 contributed to the opposite phenotype. Mechanistically, MYBL2 could bind to the promoter of its downstream target gene cell division cycle-associated protein 3 (CDCA3) and transactivate it, which in turn promoted the malignant phenotype of BLCA cells. Further investigations revealed that MYBL2 interacted with forkhead box M1 (FOXM1) to co-regulate the transcription of CDCA3. In addition, MYBL2 and CDCA3 may activate the Wnt/β-catenin signaling by inhibiting the suppressor dickkopf-1 (DKK1), thereby regulating the malignant phenotype of BLCA cells. In conclusion, the current study has identified MYBL2 as an oncogene in BLCA. MYBL2 can accelerate the proliferation and metastasis of BLCA through the transactivation of CDCA3.

2022-05-04 | GSE201979 | GEO

ChIP-seq of A673 Ewing sarcoma cells using a specific anti-MYBL2 antibody

Project description:Deciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here we demonstrate in the Ewing sarcoma model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response. We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls transcription of MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Genetic interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased proliferation and tumorigenicity of Ewing sarcoma cells. Combined RNA- and ChIP-seq experiments identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments high MYBL2 levels sensitized Ewing sarcoma cells for inhibition of its activating cyclin dependent kinase, CDK2, in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine.

2019-08-16 | GSE119971 | GEO

Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation

Project description:Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of genes down-regulated by MYCN, we generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-1 (DKK1) in both cell lines. DKK1 is a potent inhibitor of the wnt/beta-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKK1 inducible cell line, IMR32-DKK1, which showed impaired proliferation upon DKK1 expression. Surprisingly, DKK1 expression did not inhibit the canonical wnt/beta-catenin signalling, suggesting a role of DKK1 in an alternative route of the wnt pathway. Gene expression profiling of two IMR32-DKK1 clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKK1. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression. Keywords: DKK1, MYCN, neuroblastoma, Dickkopf

2007-08-24 | GSE8066 | GEO

Global binding profiles of MYBL2 and FOXM1 in lung adenocarcinoma reveal that MYBL2 regulates FOXM1 to control cell-cycle genes including CENPA [ChIP-seq]

Project description:MYBL2 is a transcription factor that has either pro-survival or anti-survival functions in a cell-type specific manner. Overexpression of MYBL2 is associated with worse survival of lung adenocarcinoma, but the mechanism by which it regulates transcription has not yet been elucidated. In this study, we found that MYBL2 mainly binds to the promoters of highly expressed genes in lung adenocarcinoma cells using ChIP-seq. Using knock-down and RNA-seq approach, we identified over a thousand of genes deregulated by MYBL2. By integrating ChIP-seq and RNA-seq data, we identified target genes of MYBL2. We revealed that FOXM1 is regulated by MYBL2 in lung adenocarcinoma cells, and FOXM1 binding sites are largely shared with MYBL2 binding sites. We treated lung adenocarcinoma cells with FDI-6, a known FOXM1 inhibitor and investigated the effect of FDI-6 in transcriptional regulation of MYBL2 and FOXM1. We found that CENPA is one of the key genes regulated by MYBL2 and FOXM1, and that it can be inhibited by FDI-6. Our signaling pathway analysis results revealed that MYBL2 and FOXM1 activate cell-cycle genes, suggesting that MYBL2 and FOXM1 act as oncogenic transcription factors in lung adenocarcinoma cells and FDI-6 could be a potential treatment of the disease.

2022-11-02 | GSE201271 | GEO

Global binding profiles of MYBL2 and FOXM1 in lung adenocarcinoma reveal that MYBL2 regulates FOXM1 to control cell-cycle genes including CENPA [RNA-seq]

2022-11-02 | GSE201270 | GEO

MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy (RNAi)

Project description:A dosage-dependent role for tumor suppressor genes in the initiation of myeloid malignancies remains controversial. Here we show that MYBL2 is expressed at sharply reduced levels in CD34+ cells from most patients with myelodysplastic syndrome (MDS; 65%; n=26). In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors led to clonal dominance by these M-bM-^@M-^\sub-haploinsufficientM-bM-^@M-^] cells, affecting all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. Thus, downregulation of MYBL2 activity to levels below those predicted by classical haploinsufficiency drives the clonal expansion of hematopoietic progenitors in a large fraction of human MDS cases. Cryopreserved CD34+ bone marrow were cultured for 24 hours, transduced with shRNA-encoding vectors and selected with Puromycin for 48 hours. Vectors shRNA 1-8 are specifically targeting MYBL2, vectors shRNA A-D encoded an irrelevant control shRNAs and one culture was left untreated (no shRNA). Cells were harvested after Puromycin selection and total RNA was prepared using Trizol (LifeTechnologies).

2013-09-15 | E-GEOD-43400 | biostudies-arrayexpress

MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy (RNA)

Project description:A dosage-dependent role for tumor suppressor genes in the initiation of myeloid malignancies remains controversial. Here we show that MYBL2 is expressed at sharply reduced levels in CD34+ cells from most patients with myelodysplastic syndrome (MDS; 65%; n=26). In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors led to clonal dominance by these M-bM-^@M-^\sub-haploinsufficientM-bM-^@M-^] cells, affecting all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. Thus, downregulation of MYBL2 activity to levels below those predicted by classical haploinsufficiency drives the clonal expansion of hematopoietic progenitors in a large fraction of human MDS cases. Total RNA was prepared from CD34+ bone marrow cells obtained from MDS patients or healthy controls.

2013-09-15 | E-GEOD-43399 | biostudies-arrayexpress

Transcription profiling of human cell lines reveals Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation

Project description:Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of genes down-regulated by MYCN, we generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-1 (DKK1) in both cell lines. DKK1 is a potent inhibitor of the wnt/ï?¢-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKK1 inducible cell line, IMR32-DKK1, which showed impaired proliferation upon DKK1 expression. Surprisingly, DKK1 expression did not inhibit the canonical wnt/ï?¢-catenin signalling, suggesting a role of DKK1 in an alternative route of the wnt pathway. Gene expression profiling of two IMR32-DKK1 clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKK1. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression. Experiment Overall Design: Single time course experiment, including 4 time points

2008-06-16 | E-GEOD-8066 | biostudies-arrayexpress

MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy (RNAi)

2013-09-15 | GSE43400 | GEO

MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy (RNA)

2013-09-15 | GSE43399 | GEO