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CircVAMP3: A circRNA with a Role in Alveolar Rhabdomyosarcoma Cell Cycle Progression.

ABSTRACT: Circular RNAs (circRNAs), a class of covalently closed RNAs formed by a back-splicing reaction, have been involved in the regulation of diverse oncogenic processes. In this article we describe circVAMP3, a novel circular RNA overexpressed in RH4, a representative cell line of alveolar rhabdomyosarcoma. We demonstrated that circVAMP3 has a differential m⁶A pattern opposed to its linear counterpart, suggesting that the two isoforms can be differently regulated by such RNA modification. Moreover, we show how circVAMP3 depletion in alveolar rhabdomyosarcoma cells can impair cell cycle progression, through the alteration of the AKT-related pathways, pointing to this non-coding RNA as a novel regulator of the alveolar rhabdomyosarcoma progression and as a putative future therapeutic target.

SUBMITTER: Rossi F

PROVIDER: S-EPMC8303801 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CircVAMP3 is a circRNA with a role in alveolar rhabdomyosarcoma cell cycle progression

Project description:Circular RNAs (circRNAs), a class of covalently closed RNA formed by a back-splicing reaction, have been involved in the regulation of diverse oncogenic processes. In this article we describe circVAMP3, a novel circular RNA overexpressed in alveolar rhabdomyosarcoma. We demonstrate that circVAMP3 has a differential m6A pattern opposed to its linear counterpart, suggesting that the two isoforms can be differently regulated by such RNA modification although their sequence similarity. Moreover, we show how circVAMP3 depletion in alveolar rhabdomyosarcoma cells can impair cell cycle progression, e.g. through the downregulation of the AKT pathway, pointing to this non-coding RNA as a novel regulator of the alveolar rhabdomyosarcoma progression and a putative future therapeutic target.

2021-08-03 | GSE174397 | GEO

CircAFF1 is a circRNA with a role in alveolar rhabdomyosarcoma cell cycle migration

Project description:Circular RNAs (circRNAs), a new division of covalently closed RNA formed by a back-splicing reaction, have been involved in the regulation of diverse processes including those that occur in the development and pathologic processes such as cancer. In this manuscript, we describe circAFF1, a circular RNA overexpressed in representative rhabdomyosarcoma cell lines. We demonstrated that circAFF1 is a cytoplasmatic circRNA and its depletion in alveolar rhabdomyosarcoma cells impacts cell homeostasis favouring cell migration, pointing to this non-coding RNA as a novel regulator of the alveolar rhabdomyosarcoma progression and as a putative future therapeutic target.

2023-08-08 | GSE214354 | GEO

CircVAMP3 is a circRNA with a role in alveolar rhabdomyosarcoma cell cycle progression

Project description:CircVAMP3 is a circRNA with a role in alveolar rhabdomyosarcoma cell cycle progression

| PRJNA729747 | ENA

CircAFF1 is a circRNA with a role in alveolar rhabdomyosarcoma cell cycle migration

Project description:CircAFF1 is a circRNA with a role in alveolar rhabdomyosarcoma cell cycle migration

| PRJNA885056 | ENA

Role of EHMT1 in Alveolar Rhabdomyosarcoma

Project description:Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma, wherein the malignant tumors arise from the myoblast like cells due to the perturbations in growth and differentiation. Alveolar rhabdomyosarcoma (ARMS) is one of the two major histological subtypes which exhibits high metastatic potential and tumor recurrence culminating in poor prognosis. In the recent past, understanding the epigenetic modifications in these tumors with less genetic alterations has shed light on the process of tumor pathogenesis and development of potential epi-drugs for the effective treatment strategies. Epigenetic regulator, Euchromatin histone lysine methyltransferase 1 (EHMT1)/G9A-like protein (GLP) and its homolog Euchromatin histone lysine methyltransferase 1 (EHMT2)/G9A has been shown to promote proliferation and inhibit differentiation in the mouse myoblast cells, independently. Also, previous study from our lab reported the overexpression of EHMT2 and molecular mechanism associated with the oncogenic phenotype in ARMS. However, expression pattern and functional role of EHMT1 in ARMS is unknown. Herein, we investigated the role of EHMT1 in ARMS. Our preliminary data indicated the overexpression of EHMT1 and the associated oncogenic phenotypes in ARMS. Although EHMT1 has shown to be upregulated and correlated with the increased disease severity in several cancers including gastric, esophagus, squamous cell carcinoma, ovarian and breast cancer, the mechanism involved in the EHMT1 mediated tumorigenesis was unclear. Therefore, through our current study we aimed to understand the expression pattern and the mechanism through which EHMT1 regulated cancer phenotypes in ARMS, for this we performed whole transcriptomic analysis in ARMS cell lines upon EHMT1 knockdown for the first time. In addition, we also compared the expression levels of EHMT1 between Human skeletal muscle myoblasts (HSMM) and ARMS patient samples (obtained from St Jude cloud database).

2021-12-08 | GSE179049 | GEO

Nox2-derived ROS in PPAR? signaling and cell-cycle progression of lung alveolar epithelial cells.

Project description:Reactive oxygen species (ROS) play important roles in peroxisome proliferator-activated receptor ? (PPAR?) signaling and cell-cycle regulation. However, the PPAR? redox-signaling pathways in lung alveolar epithelial cells remain unclear. In this study, we investigated the in vivo and in vitro effects of PPAR? activation on the levels of lung ROS production and cell-cycle progression using C57BL/6J wild-type and Nox2 knockout mice (n=10) after intraperitoneal injection of a selective PPAR? agonist (GW1929, 5 mg/kg body wt, daily) for 14 days. Compared to vehicle-treated mice, GW1929 increased significantly the levels of ROS production in wild-type lungs, and this was accompanied by significant up-regulation of PPAR?, Nox2, PCNA, and cyclin D1 and phosphorylation of ERK1/2 and p38MAPK. These effects were absent in Nox2 knockout mice. In cultured alveolar epithelial cells, GW1929 (5 ?M for 24 h) increased ROS production and promoted cell-cycle progression from G0/G1 into S and G2/M phases, and these effects were abolished by (1) adding a PPAR? antagonist (BADGE, 1 ?M), (2) knockdown of PPAR? using siRNA, or (3) knockout of Nox2. In conclusion, PPAR? activation through Nox2-derived ROS promotes cell-cycle progression in normal mouse lungs and in cultured normal alveolar epithelial cells.

| S-EPMC3157571 | biostudies-literature

Role of EHMT1 in Alveolar Rhabdomyosarcoma

Project description:Role of EHMT1 in Alveolar Rhabdomyosarcoma

| PRJNA742016 | ENA

The role of multifunctional M1 metallopeptidases in cell cycle progression.

Project description:BackgroundMetallopeptidases of the M1 family are found in all phyla (except viruses) and are important in the cell cycle and normal growth and development. M1s often have spatiotemporal expression patterns which allow for strict regulation of activity. Mutations in the genes encoding M1s result in disease and are often lethal. This family of zinc metallopeptidases all share the catalytic region containing a signature amino acid exopeptidase (GXMXN) and a zinc binding (HEXXH[18X]E) motif. In addition, M1 aminopeptidases often also contain additional membrane association and/or protein interaction motifs. These protein interaction domains may function independently of M1 enzymatic activity and can contribute to multifunctionality of the proteins.ScopeA brief review of M1 metalloproteases in plants and animals and their roles in the cell cycle is presented. In animals, human puromycin-sensitive aminopeptidase (PSA) acts during mitosis and perhaps meiosis, while the insect homologue puromycin-sensitive aminopeptidase (PAM-1) is required for meiotic and mitotic exit; the remaining human M1 family members appear to play a direct or indirect role in mitosis/cell proliferation. In plants, meiotic prophase aminopeptidase 1 (MPA1) is essential for the first steps in meiosis, and aminopeptidase M1 (APM1) appears to be important in mitosis and cell division.ConclusionsM1 metalloprotease activity in the cell cycle is conserved across phyla. The activities of the multifunctional M1s, processing small peptides and peptide hormones and contributing to protein trafficking and signal transduction processes, either directly or indirectly impact on the cell cycle. Identification of peptide substrates and interacting protein partners is required to understand M1 function in fertility and normal growth and development in plants.

| S-EPMC3091800 | biostudies-literature

PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma.

Project description:Alveolar rhabdomyosarcoma (aRMS) is an aggressive myogenic childhood malignancy, not infrequently presenting as incurable metastatic disease. To identify therapeutic targets, we performed an unbiased tyrosine kinome RNA interference screen in primary cell cultures from a genetically engineered, conditional mouse model of aRMS. We identified ephrin receptor B4 (EphB4) as a target that is widely expressed in human aRMS and that portends a poor clinical outcome in an expression level-dependent manner. We also uncovered cross-talk of this ephrin receptor with another receptor tyrosine kinase, PDGFRβ, which facilitates PDGF ligand-dependent, ephrin ligand-independent activation of EphB4 converging on the Akt and Erk1/2 pathways. Conversely, EphB4 activation by its cognate ligand, EphrinB2, did not stimulate PDGFRβ; instead, apoptosis was paradoxically induced. Finally, we showed that small-molecule inhibition of both PDGFRβ and EphB4 by dasatinib resulted in a significant decrease in tumor cell viability in vitro, as well as decreased tumor growth rate and significantly prolonged survival in vivo. To our knowledge, these results are the first to identify EphB4 and its cross-talk with PDGFRβ as unexpected vital determinants of tumor cell survival in aRMS, with EphB4 at the crux of a bivalent signaling node that is either mitogenic or proapoptotic.

| S-EPMC4035936 | biostudies-literature

Therapeutic targeting of ATR in alveolar rhabdomyosarcoma.

Project description:Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.

| S-EPMC9314382 | biostudies-literature

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