MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer

Judge, Sarah M.; Deyhle, Michael R.; Neyroud, Daria; Nosacka, Rachel L.; D’Lugos, Andrew C.; Cameron, Miles E.; Vohra, Ravneet S.; Smuder, Ashley J.; Roberts, Brandon M.; Callaway, Chandler S.; Underwood, Patrick W.; Chrzanowski, Stephen M.; Batra, Abhinandan; Murphy, Meghan; Heaven, Jonathan D.; Walter, Glenn A.; Treviño, José G.; Judge, Andrew R.

doi:10.1158/0008-5472.can-19-1558

Cited by 37 publications

(36 citation statements)

References 53 publications

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“…Its high expression was found to be associated with poor outcomes in a series of different cancers ( Nass et al, 2017 ) MYOC is a skeletal muscle hypertrophy-promoting protein that was found to be downregulated in multiple cancer cachexia mouse models. The loss of MYOC in these models could induce phenotypes such as muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration ( Judge et al, 2020 ). MEDAG is a gene involved in processes that promote adipocyte differentiation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

et al. 2021

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AimImmune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA).MethodsImmune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC.ResultsWe selected 255 patients with SARC for our analysis. The Kaplan–Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC.ConclusionThe current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

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Section: Discussionmentioning

confidence: 99%

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

et al. 2021

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“…Interestingly, MEF2 transcriptional activity and muscle atrophy can be rescued by a caMEF2 mutant that shows less propensity for co-aggregation [ 74 ]. Another recent study reported that caMEF2 prevents muscle wasting in cachectic tumor-bearing mice [ 75 ]. This study identified the myocilin gene Myoc as a transcriptional target of MEF2 and showed that loss of myocilin mediates tumor-associated muscle wasting while caMEF2 prevents concomitant Myoc downregulation.…”

Section: Transcriptional Control: Transcription Factors and Coregulatorsmentioning

confidence: 99%

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Schiaffino

Reggiani

Akimoto

et al. 2021

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101

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Skeletal muscle hypertrophy can be induced by hormones and growth factors acting directly as positive regulators of muscle growth or indirectly by neutralizing negative regulators, and by mechanical signals mediating the effect of resistance exercise. Muscle growth during hypertrophy is controlled at the translational level, through the stimulation of protein synthesis, and at the transcriptional level, through the activation of ribosomal RNAs and muscle-specific genes. mTORC1 has a central role in the regulation of both protein synthesis and ribosomal biogenesis. Several transcription factors and co-activators, including MEF2, SRF, PGC-1α4, and YAP promote the growth of the myofibers. Satellite cell proliferation and fusion is involved in some but not all muscle hypertrophy models.

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“…In further support of FoxP1 as a negative regulator of MEF2, we found that FoxP1 was also sufficient to repress a MEF2‐dependent luciferase reporter. These findings are noteworthy, because we recently showed that MEF2c gain‐of‐function protects against cancer‐associated muscle wasting and weakness, 68 and highlight FoxP1 up‐regulation as a novel mechanism that contributes to the disruption of MEF2 target gene transcription during cancer cachexia.…”

Section: Discussionmentioning

confidence: 85%

“…low skeletal muscle index) (Figure 10A-B). Moreover, extraction of skeletal muscle microarray data from a larger cohort of PDAC patients 20,68 further revealed a positive correlation between the mRNA levels of FOXP1 and body mass loss (Figure 10C), and a negative correlation between the mRNA levels of FOXP1 and skeletal muscle index (Figure 10D). In support of these findings, FOXP1 mRNA levels were significantly higher in PDAC patients classified as cachectic compared with weight-stable non-cancer controls (Figure 10E), which aligns with our finding of increased abundance of FOXP1 protein.…”

Section: Foxp1 Is Increased In Skeletal Muscle Of Cachectic Cancer Pamentioning

confidence: 94%

FoxP1 is a transcriptional repressor associated with cancer cachexia that induces skeletal muscle wasting and weakness

Neyroud

Nosacka

Callaway

et al. 2021

J cachexia sarcopenia muscle

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Background Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein, we investigated the biological significance of Forkhead box P1 (FoxP1), a transcriptional repressor that we demonstrate is up-regulated in skeletal muscle in multiple models of cancer cachexia and in cachectic cancer patients. Methods Inducible, skeletal muscle-specific FoxP1 over-expressing (FoxP1 iSkmTg/Tg ) mice were generated through crossing conditional Foxp1a transgenic mice with HSA-MCM mice that express tamoxifen-inducible Cre recombinase under control of the skeletal muscle actin promoter. To determine the requirement of FoxP1 for cancer-induced skeletal muscle wasting, FoxP1-shRNA was packaged and targeted to muscles using AAV9 delivery prior to inoculation of mice with Colon-26 Adenocarcinoma (C26) cells. Results Up-regulation of FoxP1 in adult skeletal muscle was sufficient to induce features of cachexia, including 15% reduction in body mass (P < 0.05), and a 16-27% reduction in skeletal muscle mass (P < 0.05) that was characterized by a 20% reduction in muscle fibre cross-sectional area of type IIX/B muscle fibres (P = 0.020). Skeletal muscles from FoxP1 iSkmTg/Tg mice also showed significant damage and myopathy characterized by the presence of centrally nucleated myofibres, extracellular matrix expansion, and were 19-26% weaker than controls (P < 0.05). Transcriptomic analysis revealed FoxP1 as a potent transcriptional repressor of skeletal muscle gene expression, with enrichment of pathways related to skeletal muscle structure and function, growth signalling, and cell quality control. Because FoxP1 functions, at least in part, as a transcriptional repressor through its interaction with histone deacetylase proteins, we treated FoxP1 iSkmTg/Tg mice with Trichostatin A, and found that this completely prevented the loss of muscle mass (p = 0.007) and fibre atrophy (P < 0.001) in the tibialis anterior. In the context of cancer, FoxP1 knockdown blocked the cancer-induced repression of myocyte enhancer factor 2 (MEF2)-target genes critical to muscle differentiation and repair, improved muscle ultrastructure, and attenuated muscle fibre atrophy by 50% (P < 0.05). Conclusions In summary, we identify FoxP1 as a novel repressor of skeletal muscle gene expression that is increased in cancer cachexia, whose up-regulation is sufficient to induce skeletal muscle wasting and weakness, and required for the normal wasting response to cancer.

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MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer

Cited by 37 publications

References 53 publications

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma

Molecular Mechanisms of Skeletal Muscle Hypertrophy

FoxP1 is a transcriptional repressor associated with cancer cachexia that induces skeletal muscle wasting and weakness

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