MYF6 suppresses cell growth through inhibition of Akt and Wnt signaling in ER-positive breast cancer
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ABSTRACT:
PROVIDER: PRJNA779631 | ENA |
REPOSITORIES: ENA
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Project description:Background: Proliferation is an important hallmark of cancer development and progression. Tumor growth rate significantly influences the course of the disease, and patients with tumors that have a high proliferation rate have an increased risk (10-20%) of metastasis and death. The genomic region encoding the transcription factor MYF6 is often altered in breast cancer, and alterations in MYF6 methylation have been linked to several different cancer types. However, the functional role of MYF6 in cancer remain unknown. Here, we have dissected the functional role of MYF6 in ER+ breast cancer. Methods: We analyzed cancer cell growth, proliferation, apoptosis, in vivo tumor formation, EMT phenotype and BCSC propagation in MCF7 and T47D ER+ breast cancer models with inducuble MYF6 overexpression or MYF6 knockdown. Additionally, we performed detailed molecular profiling and network analysis, and Western blot validation of identified targets. Results: We show that MYF6 suppresses PI3K/Akt/mTOR and Wnt pathway signaling, two important pathways of cell proliferation, and suppression was accompanied by reduced cell growth in vitro and in vivo, and G0/G1 phase cell cycle arrest. MYF6 also induced an EMT phenotype and forced the cells into a cancer stem cell-like state, leading to resistance to -irradiation. Network analysis of molecular profiling data revealed that MYF6 activates hypoxia signaling and HIF1A was identified as a downstream target and an upstream regulator of MYF6. Conclusion: Our results suggest both a tumor-suppressive and oncogenic role of MYF6 in ER+ breast cancer, and we theorize that, subject to the presence or absence of yet unidentified cellular factors, MYF6 can switch from a growth-inhibiting tumor suppressor to an oncogene state, associated with cancer stem cells and treatment resistance.
2023-01-31 | GSE188537 | GEO
Project description:Background: Proliferation is an important hallmark of cancer development and progression. Tumor growth rate significantly influences the course of the disease, and patients with tumors that have a high proliferation rate have an increased risk (10-20%) of metastasis and death. The genomic region encoding the transcription factor MYF6 is often altered in breast cancer, and alterations in MYF6 methylation have been linked to several different cancer types. However, the functional role of MYF6 in cancer remain unknown. Here, we have dissected the functional role of MYF6 in ER+ breast cancer. Methods: We analyzed cancer cell growth, proliferation, apoptosis, in vivo tumor formation, EMT phenotype and BCSC propagation in MCF7 and T47D ER+ breast cancer models with inducuble MYF6 overexpression or MYF6 knockdown. Additionally, we performed detailed molecular profiling and network analysis, and Western blot validation of identified targets. Results: We show that MYF6 suppresses PI3K/Akt/mTOR and Wnt pathway signaling, two important pathways of cell proliferation, and suppression was accompanied by reduced cell growth in vitro and in vivo, and G0/G1 phase cell cycle arrest. MYF6 also induced an EMT phenotype and forced the cells into a cancer stem cell-like state, leading to resistance to -irradiation. Network analysis of molecular profiling data revealed that MYF6 activates hypoxia signaling and HIF1A was identified as a downstream target and an upstream regulator of MYF6. Conclusion: Our results suggest both a tumor-suppressive and oncogenic role of MYF6 in ER+ breast cancer, and we theorize that, subject to the presence or absence of yet unidentified cellular factors, MYF6 can switch from a growth-inhibiting tumor suppressor to an oncogene state, associated with cancer stem cells and treatment resistance.
2023-01-31 | GSE188505 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-01-31 | GSE188609 | GEO
Project description:In metazoans, skeletal muscle evolved to contract and produce force. Recent experimental evidence, however, suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of muscle-derived cytokines and growth factors, collectively called myokines. The mechanisms that regulate myokine production and their effect on the resident stem cell population inskeletal muscle remain unknown. Here, we report that in adult skeletal muscle, Myf6/MRF4 is a major regulator of myokine expression. Genetic deletion of Myf6 in skeletal muscle leads to reduction of the muscle stem cell (MuSCs) pool in adult mice in a myokine-dependent manner but, surprisingly, does not disrupt muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is a direct regulator of many myokines and muscle-secreted proteins, including ligands for canonical signaling pathways such as EGFR and VEGFR. Consequently, in Myf6-deficient animals,MuSCs increasingly break quiescence, but can nevertheless undergo differentiation. Lastly, we show that Myf6 and its gene network rapidly respondto aerobic and anaerobic exercise. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool and skeletal muscle function via myokine signaling.
2020-10-02 | GSE133505 | GEO
Project description:CMTM6 drives cisplatin resistance by regulating AKT mediated Wnt signaling
| PRJEB39795 | ENA
Project description:Padala2017- ERK, PI3K/Akt and Wnt signalling
network (normal)
Crosstalk model of the ERK, Wnt and Akt
signalling pathways under normal condition.
This model is described in the article:
Cancerous perturbations
within the ERK, PI3K/Akt, and Wnt/?-catenin signaling network
constitutively activate inter-pathway positive feedback
loops.
Padala RR, Karnawat R, Viswanathan
SB, Thakkar AV, Das AB.
Mol Biosyst 2017 May; 13(5):
830-840
Abstract:
Perturbations in molecular signaling pathways are a result
of genetic or epigenetic alterations, which may lead to
malignant transformation of cells. Despite cellular robustness,
specific genetic or epigenetic changes of any gene can trigger
a cascade of failures, which result in the malfunctioning of
cell signaling pathways and lead to cancer phenotypes. The
extent of cellular robustness has a link with the architecture
of the network such as feedback and feedforward loops.
Perturbation in components within feedback loops causes a
transition from a regulated to a persistently activated state
and results in uncontrolled cell growth. This work represents
the mathematical and quantitative modeling of ERK, PI3K/Akt,
and Wnt/?-catenin signaling crosstalk to show the dynamics of
signaling responses during genetic and epigenetic changes in
cancer. ERK, PI3K/Akt, and Wnt/?-catenin signaling crosstalk
networks include both intra and inter-pathway feedback loops
which function in a controlled fashion in a healthy cell. Our
results show that cancerous perturbations of components such as
EGFR, Ras, B-Raf, PTEN, and components of the destruction
complex cause extreme fragility in the network and
constitutively activate inter-pathway positive feedback loops.
We observed that the aberrant signaling response due to the
failure of specific network components is transmitted
throughout the network via crosstalk, generating an additive
effect on cancer growth and proliferation.
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Chelliah V et al. BioModels: ten-year
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issue):D542-8.
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neighbouring rights to this encoded model have been dedicated to
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2024-09-02 | BIOMD0000000648 | BioModels
Project description:Conversion of fibroblasts into skeletal muscle cells by overexpression of the transcription factor MyoD has been widely employed over past decades in a multitude of experimental settings. However, the potential of additional myogenic regulatory factors such as Myf5, Myf6 and Myog to elicit a myogenic conversion has been significantly less studied. To address this disparity, we set out to investigate the role of MRFs in fibroblast conversion into skeletal muscle stem and differentiated cells. Surprisingly, we found that Myf6, a transcription factor associated with postnatal late-stage myogenesis, efficiently converted fibroblasts into myotubes alone, or alternatively into expandable Pax7-expressing induced myogenic progenitor cells (iMPCs) in the presence of defined small molecules. To investigate reprogramming dynamics in a tightly regulated system, we generated an inducible Myf6 overexpression transgenic mouse model, which enabled dissection of transcription and epigenetic dynamics unique to iMPC formation. Mechanistically, we characterized the chromatin binding of Myf6, as well as its protein binding partners, during iMPC reprogramming and conventional transdifferentiation, revealing shared and different targets and binding partners. To further investigate its role, we surprisingly found that endogenous Myf6 is dispensable for iMPC formation by MyoD and small molecules. In accordance with this observation, we demonstrated that subjecting MyoD-KO fibroblasts to reprogramming with Myf6 and small molecules gave rise to expandable MyoD-KO iMPCs, indicating that MyoD is similarly dispensable for iMPC formation and self-renewal. Multi-omics analyses of Myf6-derived MyoD-KO iMPCs uncovered upregulated genes that compensated for the lack of MyoD, whose downregulation during iMPC production mitigated Pax7 expression, highlighting their roles as reprogramming regulators. Collectively, these results illustrate a redundancy between MRFs’ function in myogenic cellular conversions, highlighting an unexpected potency for Myf6 in the induction of a muscle stem cell fate in vitro.
2026-03-04 | GSE291099 | GEO
Project description:Conversion of fibroblasts into skeletal muscle cells by overexpression of the transcription factor MyoD has been widely employed over past decades in a multitude of experimental settings. However, the potential of additional myogenic regulatory factors such as Myf5, Myf6 and Myog to elicit a myogenic conversion has been significantly less studied. To address this disparity, we set out to investigate the role of MRFs in fibroblast conversion into skeletal muscle stem and differentiated cells. Surprisingly, we found that Myf6, a transcription factor associated with postnatal late-stage myogenesis, efficiently converted fibroblasts into myotubes alone, or alternatively into expandable Pax7-expressing induced myogenic progenitor cells (iMPCs) in the presence of defined small molecules. To investigate reprogramming dynamics in a tightly regulated system, we generated an inducible Myf6 overexpression transgenic mouse model, which enabled dissection of transcription and epigenetic dynamics unique to iMPC formation. Mechanistically, we characterized the chromatin binding of Myf6, as well as its protein binding partners, during iMPC reprogramming and conventional transdifferentiation, revealing shared and different targets and binding partners. To further investigate its role, we surprisingly found that endogenous Myf6 is dispensable for iMPC formation by MyoD and small molecules. In accordance with this observation, we demonstrated that subjecting MyoD-KO fibroblasts to reprogramming with Myf6 and small molecules gave rise to expandable MyoD-KO iMPCs, indicating that MyoD is similarly dispensable for iMPC formation and self-renewal. Multi-omics analyses of Myf6-derived MyoD-KO iMPCs uncovered upregulated genes that compensated for the lack of MyoD, whose downregulation during iMPC production mitigated Pax7 expression, highlighting their roles as reprogramming regulators. Collectively, these results illustrate a redundancy between MRFs’ function in myogenic cellular conversions, highlighting an unexpected potency for Myf6 in the induction of a muscle stem cell fate in vitro.
2026-03-04 | GSE291102 | GEO
Project description:Conversion of fibroblasts into skeletal muscle cells by overexpression of the transcription factor MyoD has been widely employed over past decades in a multitude of experimental settings. However, the potential of additional myogenic regulatory factors such as Myf5, Myf6 and Myog to elicit a myogenic conversion has been significantly less studied. To address this disparity, we set out to investigate the role of MRFs in fibroblast conversion into skeletal muscle stem and differentiated cells. Surprisingly, we found that Myf6, a transcription factor associated with postnatal late-stage myogenesis, efficiently converted fibroblasts into myotubes alone, or alternatively into expandable Pax7-expressing induced myogenic progenitor cells (iMPCs) in the presence of defined small molecules. To investigate reprogramming dynamics in a tightly regulated system, we generated an inducible Myf6 overexpression transgenic mouse model, which enabled dissection of transcription and epigenetic dynamics unique to iMPC formation. Mechanistically, we characterized the chromatin binding of Myf6, as well as its protein binding partners, during iMPC reprogramming and conventional transdifferentiation, revealing shared and different targets and binding partners. To further investigate its role, we surprisingly found that endogenous Myf6 is dispensable for iMPC formation by MyoD and small molecules. In accordance with this observation, we demonstrated that subjecting MyoD-KO fibroblasts to reprogramming with Myf6 and small molecules gave rise to expandable MyoD-KO iMPCs, indicating that MyoD is similarly dispensable for iMPC formation and self-renewal. Multi-omics analyses of Myf6-derived MyoD-KO iMPCs uncovered upregulated genes that compensated for the lack of MyoD, whose downregulation during iMPC production mitigated Pax7 expression, highlighting their roles as reprogramming regulators. Collectively, these results illustrate a redundancy between MRFs’ function in myogenic cellular conversions, highlighting an unexpected potency for Myf6 in the induction of a muscle stem cell fate in vitro.
2026-03-04 | GSE291100 | GEO
Project description:Conversion of fibroblasts into skeletal muscle cells by overexpression of the transcription factor MyoD has been widely employed over past decades in a multitude of experimental settings. However, the potential of additional myogenic regulatory factors such as Myf5, Myf6 and Myog to elicit a myogenic conversion has been significantly less studied. To address this disparity, we set out to investigate the role of MRFs in fibroblast conversion into skeletal muscle stem and differentiated cells. Surprisingly, we found that Myf6, a transcription factor associated with postnatal late-stage myogenesis, efficiently converted fibroblasts into myotubes alone, or alternatively into expandable Pax7-expressing induced myogenic progenitor cells (iMPCs) in the presence of defined small molecules. To investigate reprogramming dynamics in a tightly regulated system, we generated an inducible Myf6 overexpression transgenic mouse model, which enabled dissection of transcription and epigenetic dynamics unique to iMPC formation. Mechanistically, we characterized the chromatin binding of Myf6, as well as its protein binding partners, during iMPC reprogramming and conventional transdifferentiation, revealing shared and different targets and binding partners. To further investigate its role, we surprisingly found that endogenous Myf6 is dispensable for iMPC formation by MyoD and small molecules. In accordance with this observation, we demonstrated that subjecting MyoD-KO fibroblasts to reprogramming with Myf6 and small molecules gave rise to expandable MyoD-KO iMPCs, indicating that MyoD is similarly dispensable for iMPC formation and self-renewal. Multi-omics analyses of Myf6-derived MyoD-KO iMPCs uncovered upregulated genes that compensated for the lack of MyoD, whose downregulation during iMPC production mitigated Pax7 expression, highlighting their roles as reprogramming regulators. Collectively, these results illustrate a redundancy between MRFs’ function in myogenic cellular conversions, highlighting an unexpected potency for Myf6 in the induction of a muscle stem cell fate in vitro.
2026-03-04 | GSE291101 | GEO