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1.
Cell Rep ; 40(9): 111267, 2022 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-36044855

RESUMEN

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. The alveolar fusion positive subtype (FP-RMS) is the most aggressive and is mainly caused by the expression of PAX3/7-FOXO1 oncoproteins, which are challenging pharmacological targets. Here, we show that the DEAD box RNA helicase 5 (DDX5) is overexpressed in alveolar RMS cells and that its depletion and pharmacological inhibition decrease FP-RMS viability and slow tumor growth in xenograft models. Mechanistically, we provide evidence that DDX5 functions upstream of the EHMT2/AKT survival signaling pathway, by directly interacting with EHMT2 mRNA, modulating its stability and consequent protein expression. We show that EHMT2 in turns regulates PAX3-FOXO1 activity in a methylation-dependent manner, thus sustaining FP-RMS myoblastic state. Together, our findings identify another survival-promoting loop in FP-RMS and highlight DDX5 as a potential therapeutic target to arrest RMS growth.


Asunto(s)
ARN Helicasas DEAD-box , Rabdomiosarcoma Alveolar , Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Línea Celular Tumoral , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Proteínas de Fusión Oncogénica/metabolismo , Factores de Transcripción Paired Box/genética , ARN Helicasas/metabolismo , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/metabolismo , Rabdomiosarcoma Alveolar/patología
2.
Bioorg Med Chem Lett ; 72: 128858, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35718104

RESUMEN

A new series of in vitro potent and highly selective histone methyl transferase enzyme G9a inhibitors was obtained. In particular, compound 2a, one the most potent G9a inhibitor identified, was endowed with >130-fold selectivity over GLP and excellent ligand efficiency. Therefore, it may represent a valuable tool compound to validate the role of highly selective G9a inhibitors in different pathological conditions. When 2a was characterized in vitro in cellular models of skeletal muscle differentiation, a relevant increase of myofibers' size and reduction of the fibroadipogenic infiltration were observed, further confirming the therapeutic potential of selective G9a inhibitors for the treatment of Duchenne muscle dystrophy.


Asunto(s)
N-Metiltransferasa de Histona-Lisina , Histonas , Inhibidores Enzimáticos/farmacología
3.
Life (Basel) ; 12(4)2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35455028

RESUMEN

Duchenne muscular dystrophy (DMD) is an X-linked disease, caused by a mutant dystrophin gene, leading to muscle membrane instability, followed by muscle inflammation, infiltration of pro-inflammatory macrophages and fibrosis. The calcium-activated potassium channel type 3.1 (KCa3.1) plays key roles in controlling both macrophage phenotype and fibroblast proliferation, two critical contributors to muscle damage. In this work, we demonstrate that pharmacological blockade of the channel in the mdx mouse model during the early degenerative phase favors the acquisition of an anti-inflammatory phenotype by tissue macrophages and reduces collagen deposition in muscles, with a concomitant reduction of muscle damage. As already observed with other treatments, no improvement in muscle performance was observed in vivo. In conclusion, this work supports the idea that KCa3.1 channels play a contributing role in controlling damage-causing cells in DMD. A more complete understanding of their function could lead to the identification of novel therapeutic approaches.

4.
Trends Genet ; 38(5): 501-513, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35078651

RESUMEN

Muscle stem cells (MuSCs) are responsible for skeletal muscle homeostasis and repair. In response to extracellular cues, MuSCs activate from quiescence, expand, differentiate into mature myofibers, and self-renew within their regenerative niche. These steps are accomplished by the dynamic action of different chromatin-modifying enzymes that, cooperating with myogenic transcription factors, coordinately regulate defined transcriptional programs. Here, we review the current knowledge on the epigenetic dynamics that allow MuSCs' fate decisions. We describe the emerging mechanisms showing how chromatin topology impacts the 3D genome architecture of MuSCs during myogenesis. Because these processes contribute to shape and maintain cell identity, we highlight how defects in proper epigenetic control of MuSCs' fate decisions underlie the pathogenesis of muscle diseases, causing the acquisition of derailed cell fates and the incapacity to properly self-renew.


Asunto(s)
Músculo Esquelético , Células Madre , Diferenciación Celular/genética , Cromatina/genética , Epigénesis Genética , Músculo Esquelético/fisiología
5.
Sci Adv ; 7(23)2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34078594

RESUMEN

H3K9 methylation maintains cell identity orchestrating stable silencing and anchoring of alternate fate genes within the heterochromatic compartment underneath the nuclear lamina (NL). However, how cell type-specific genomic regions are specifically targeted to the NL is still elusive. Using fibro-adipogenic progenitors (FAPs) as a model, we identified Prdm16 as a nuclear envelope protein that anchors H3K9-methylated chromatin in a cell-specific manner. We show that Prdm16 mediates FAP developmental capacities by orchestrating lamina-associated domain organization and heterochromatin sequestration at the nuclear periphery. We found that Prdm16 localizes at the NL where it cooperates with the H3K9 methyltransferases G9a/GLP to mediate tethering and silencing of myogenic genes, thus repressing an alternative myogenic fate in FAPs. Genetic and pharmacological disruption of this repressive pathway confers to FAP myogenic competence, preventing fibro-adipogenic degeneration of dystrophic muscles. In summary, we reveal a druggable mechanism of heterochromatin perinuclear sequestration exploitable to reprogram FAPs in vivo.

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