The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the <i>myostatin</i> and <i>c-Met</i> genes and regulates skeletal muscle atrophy

Proserpio, Valentina; Fittipaldi, Raffaella; Ryall, James G.; Sartorelli, Vittorio; Caretti, Giuseppina

doi:10.1101/gad.217240.113

Cited by 82 publications

(87 citation statements)

References 77 publications

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“…Treating rats with the glucocorticoid receptor antagonist RU486 prevented this increase in myostatin expression 66 . A similar increase in myostatin mRNA levels was also observed after dexamethasone treatment in cultured myotubes 120,121 and in the muscles of mice 122 . Although glucocorticoid receptor antagonists or adrenalectomy can prevent muscle wasting in models of fasting and cancer, other studies found no beneficial effect of these drugs on muscle wasting following burn injury 123 or uraemia 124 , and the loss of adrenal steroids and their many protective functions was deleterious to the stressed individual.…”

Section: Muscle Atrophy During Systemic Diseasesupporting

confidence: 72%

Muscle wasting in disease: molecular mechanisms and promising therapies

Cohen

Nathan

Goldberg

2014

Nat Rev Drug Discov

878

850

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Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.

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Section: Muscle Atrophy During Systemic Diseasesupporting

confidence: 72%

Muscle wasting in disease: molecular mechanisms and promising therapies

Cohen

Nathan

Goldberg

2014

Nat Rev Drug Discov

878

850

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“…BETi exhibit broad transcriptional effects by targeting the general transcriptional elongation factor p-TEFb's interplay with Brd4. It is possible that systemic features of cancer such as inflammation (46) and muscle wasting by glucocorticosteroid treatment (47), known to be mediated by transcriptional elongation, could be targeted by BETi too for the benefit of cancer patients. Importantly, however, early trials will have to determine whether a combination treatment using BETi and HDACi will be tolerated in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Bhadury

Nilsson

Muralidharan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

198

149

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The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myctransgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.T he bromodomain and extraterminal (BET) domain family of proteins Brd2, Brd3, Brd4, and BrdT bind via their tandem bromodomains (BD1 and BD2) to acetylated lysines in histones and other proteins (1). On binding, they regulate the transcription of genes critical for cell-cycle progression and apoptosis. Therefore, BET proteins have emerged as interesting proteins for targeted intervention of cancer.Recently, the small-molecule BET inhibitor (+)-JQ-1 (hereafter JQ1) was found to be a potent and specific suppressor of B cell-lineage malignancies (2, 3). In acute myelogenous leukemia, BRD4 is essential for tumor maintenance, and JQ1 recapitulates the effects of RNA interference of BRD4 (4, 5). JQ1 was subsequently shown to have an antiproliferative effect in other hematological malignancies and solid organ tumors including glioblastoma, prostate cancer, and neuroblastoma (6-10). The current model of how BET inhibitors (BETi) inhibit tumor cell proliferation places inhibition of MYC as mediating activity in lymphoid tumors, with Myc-independent activity in some solid tumor types such as lung adenocarcinoma (11). However, it has not been clear in hematopoietic tumor types whether the antiproliferative effects of BETi are mediated by suppression of MYC expression or whether effects on MYC are a correlative bystander of the mechanism, perhaps useful as a biomarker but not necessarily mechanistic (12).We have assessed the effect of RVX2135, a novel and orally bioavailable selective inhibitor of Brd2, Brd3, Brd4, and BrdT, in in vitro and in vivo models of Myc-induced lymphoma. We find that the effects are mediated by broad transcriptional changes and that these are genetically and functionally linked to histone deacetylase inhibitors. Results RVX2135 Blocks Proliferation of Myc-Induced Mouse Lymphoma Cellsand Induces Caspase-Dependent Apoptosis. RVX2135 is a novel small-molecule BET bromodoma...

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“…DNA binding to the N-lobe has been shown to enhance SMYD3 methyltransferase activity [18]. The interaction of SMYD3 with BRD4 mediates the recruitment of transcriptional cofactors at the myostatin gene and regulates skeletal muscle atrophy [8]. SMYD3 interacts with PC4 in tumor cells and such interaction stimulates oncogenic gene expression through deposition of H3K4 tri-methylation [7].…”

Section: Discussionmentioning

confidence: 99%

New open conformation of SMYD3 implicates conformational selection and allostery

et al. 2016

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SMYD3 plays a key role in cancer cell viability, adhesion, migration and invasion. SMYD3 promotes formation of inducible regulatory T cells and is involved in reducing autoimmunity. However, the nearly “closed” substrate-binding site and poor in vitro H3K4 methyltransferase activity have obscured further understanding of this oncogenically related protein. Here we reveal that SMYD3 can adopt an “open” conformation using molecular dynamics simulation and small-angle X-ray scattering. This ligand-binding-capable open state is related to the crystal structure-like closed state by a striking clamshell-like inter-lobe dynamics. The two states are characterized by many distinct structural and dynamical differences and the conformational transition pathway is mediated by a reversible twisting motion of the C-terminal domain (CTD). The spontaneous transition from the closed to open states suggests two possible, mutually non-exclusive models for SMYD3 functional regulation and the conformational selection mechanism and allostery may regulate the catalytic or ligand binding competence of SMYD3. This study provides an immediate clue to the puzzling role of SMYD3 in epigenetic gene regulation.

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The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy

Cited by 82 publications

References 77 publications

Muscle wasting in disease: molecular mechanisms and promising therapies

Muscle wasting in disease: molecular mechanisms and promising therapies

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

New open conformation of SMYD3 implicates conformational selection and allostery

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