Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma

Altahan, Alaa; Sarkis, Omar; Harajly, Mohamad; Baghdadi, Omar Kebbe; Zibara, Kazem; Boulos, Fouad; Dighe, Dipti; Kregel, Steven; Bazarbachi, Ali; El-Sabban, Marwan; Skapek, Stephen X.; Saab, Raya

doi:10.1002/pbc.23246

Cited by 13 publications

(14 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such cooperative binding is thought to increase specificity [43]. However, a well-known feature of cooperative binding (high Hill coefficient) is a narrow input dynamic range [43]. NAR is a simple way to provide wide input dynamic range, while maintaining cooperativity at the level of regulator binding.…”

Section: Discussionmentioning

confidence: 99%

Negative auto-regulation increases the input dynamic-range of the arabinose system of Escherichia coli

et al. 2011

View full text Add to dashboard Cite

BackgroundGene regulation networks are made of recurring regulatory patterns, called network motifs. One of the most common network motifs is negative auto-regulation, in which a transcription factor represses its own production. Negative auto-regulation has several potential functions: it can shorten the response time (time to reach halfway to steady-state), stabilize expression against noise, and linearize the gene's input-output response curve. This latter function of negative auto-regulation, which increases the range of input signals over which downstream genes respond, has been studied by theory and synthetic gene circuits. Here we ask whether negative auto-regulation preserves this function also in the context of a natural system, where it is embedded within many additional interactions. To address this, we studied the negative auto-regulation motif in the arabinose utilization system of Escherichia coli, in which negative auto-regulation is part of a complex regulatory network.ResultsWe find that when negative auto-regulation is disrupted by placing the regulator araC under constitutive expression, the input dynamic range of the arabinose system is reduced by 10-fold. The apparent Hill coefficient of the induction curve changes from about n = 1 with negative auto-regulation, to about n = 2 when it is disrupted. We present a mathematical model that describes how negative auto-regulation can increase input dynamic-range, by coupling the transcription factor protein level to the input signal.ConclusionsHere we demonstrate that the negative auto-regulation motif in the native arabinose system of Escherichia coli increases the range of arabinose signals over which the system can respond. In this way, negative auto-regulation may help to increase the input dynamic-range while maintaining the specificity of cooperative regulatory systems. This function may contribute to explaining the common occurrence of negative auto-regulation in biological systems.

show abstract

Section: Discussionmentioning

confidence: 99%

Negative auto-regulation increases the input dynamic-range of the arabinose system of Escherichia coli

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Cells were lysed on ice for 15 min in Universal Lysis Buffer as in our previous studies, and protein was quantified by Bradford assay (Bio‐Rad, Richmond, CA). Equivalent amounts of protein were fractionated by 6–12% SDS‐PAGE and transferred to polyvinylidene difluoride membranes (Bio‐Rad).…”

Section: Methodsmentioning

confidence: 99%

“…Retinoic acid is a morphogen and a major regulator of cellular proliferation, apoptosis and differentiation, and has been investigated as differentiation therapy in multiple types of cancer, contributing to improved outcomes in other primitive tumors of childhood, such as acute promyelocytic leukemia and neuroblastoma . In RMS, retinoic acid has shown some activity in inhibiting proliferation and inducing differentiation in vitro , however the effects are of low magnitude, and do not translate into tumor control in vivo in mouse xenograft studies, partly due to incomplete cell cycle exit despite evidence of enhanced differentiation . More potent synthetic retinoids have been developed, and some were found to exhibit mechanisms of action independent of retinoic acid receptor signaling pathway, resulting in growth inhibitory and proapoptotic activity .…”

mentioning

confidence: 99%

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

Basma

Ghayad

Rammal

et al. 2015

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E23-(4 0 -hydroxyl-3 0 -adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma, and the third most common solid tumor in children. 1 It accounts for 6% of all childhood cancers and approximately 40% of soft tissue sarcomas. 2,3 RMS likely arises from primitive mesenchymal progenitors that have undergone a limited program of myogenic differentiation, because of the expression of skeletal myogenic proteins in RMS tumors. 1,4 Rhabdomyosarcoma occurs in two major histological subtypes: embryonal (ERMS) and alveolar (ARMS) histologies. 1,4 ARMS is associated with a chromosomal translocation between the PAX3 or PAX7 and FOXO1 genes in approximately 55 and 22% of cases, respectively. 5 Patients presenting with ARMS tumors usually have a worse prognosis as compared to ERMS. The PAX-FOXO1 fusion transcript has been shown to exhibit a more potent transcriptional activation function than the PAX proteins alone, 6 and contributes to the invasive phenotype of ARMS, 7,8 making it an interesting target for therapeutic intervention. 9 Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, limited improvements in survival have been made for patients with advanced-stage disease or recurrent RMS over the past 10 years. [10][11][12] This underlies the need for novel therapeutic approaches. 10,13 Retinoic acid is a morphogen and a major regulator of cellular proliferation, apoptosis and differentiation, 14 and has been investigated as differentiation therapy in multiple types of cancer, contributi...

show abstract

“…While the precise mechanism of differentiation inhibition is uncertain, it is believed that the relative abundance of MYOD1 activating or inhibiting E-protein heterodimer partners in RMS is shifted toward repressive heterodimers (Yang et al, 2009). Overcoming the terminal differentiation block in RMS would open the door for differentiation therapy, which aims to halt tumor progression by forcing the cells to differentiate into nondividing muscle fibers (Al-Tahan et al, 2012;Saab et al, 2011). However, our understanding of the mechanisms underlying this differentiation block in RMS remains insufficient to achieve better treatments.…”

Section: Significancementioning

confidence: 99%

The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation

et al. 2014

View full text Add to dashboard Cite

The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.

show abstract

Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma

Cited by 13 publications

References 36 publications

Negative auto-regulation increases the input dynamic-range of the arabinose system of Escherichia coli

Negative auto-regulation increases the input dynamic-range of the arabinose system of Escherichia coli

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation

Contact Info

Product

Resources

About