Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma

Pomella, Silvia; Sreenivas, Prethish; Gryder, Berkley E.; Wang, Long; Milewski, David; Cassandri, Matteo; Baxi, Kunal; Hensch, Nicole R.; Carcarino, Elena; Song, Young K.; Chou, Hsien Chao; Yohe, Marielle E.; Amadio, Bruno; Caruana, Ignazio; Stefanis, Cristiano De; Vito, Rita De; Locatelli, Franco; Chen, Yidong; Chen, Eleanor; Houghton, Peter J.; Khan, Javed; Rota, Rossella; Ignatius, Myron S.

doi:10.1038/s41467-020-20386-8

Cited by 36 publications

(77 citation statements)

References 49 publications

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“…Perhaps there are severe implications for this conceptual framework as well, such that an oncogene with pioneer function may be independent of the motif abundance or the cell of origin. Increasing evidence suggests that low mutational burden tumors are driven from epigenetic alterations ( Boone et al., 2021 ; Lin et al, 2019 ; Pomella et al., 2021 ; Sunkel et al., 2021 ). It will be important to understand how these chromatin-level changes are translated into stable transcriptional states.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study elegantly showed MYOD as a key dependency in a highly aggressive pediatric muscle tumor, rhabdomyosarcoma (RMS) ( Dharia et al., 2021 ). Mechanistically, there is evidence that this MYOD dependency in RMS is linked to activation of SNAI2 transcription ( Pomella et al., 2021 ). While wild-type MYOD can serve as a tumor driver in RMS ( Dharia et al., 2021 ; Gryder et al., 2019 ), mutant MYOD has been shown as a driver in a subtype of highly aggressive rhabdomyosarcomas with poorest clinical outcomes ( Kohsaka et al., 2014 ; Shern et al., 2014 , 2021 ).…”

Section: Pioneer Function and Cell Statementioning

confidence: 99%

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Pioneer factors in development and cancer

Sunkel

2021

iScience

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Summary Transcription factors (TFs) are essential mediators of epigenetic regulation and modifiers of penetrance. Studies from the past decades have revealed a sub-class of TF that is capable of remodeling closed chromatin states through targeting nucleosomal motifs. This pioneer factor (PF) class of chromatin remodeler is ATP independent in its roles in epigenetic initiation, with nucleosome-motif recognition and association with repressive chromatin regions. Increasing evidence suggests that the fundamental properties of PFs can be coopted in human cancers. We explore the role of PFs in the larger context of tissue-specific epigenetic regulation. Moreover, we highlight an emerging class of chimeric PF derived from translocation partners in human disease and PFs associated with rare tumors. In the age of site-directed genome editing and targeted protein degradation, increasing our understanding of PFs will provide access to next-generation therapy for human disease driven from altered transcriptional circuitry.

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Section: Discussionmentioning

confidence: 99%

Section: Pioneer Function and Cell Statementioning

confidence: 99%

Pioneer factors in development and cancer

Sunkel

2021

iScience

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“…RD (ERMS) and RH30 (ARMS) human cell lines were purchased from American Type Culture Collection (Manassas, VA, USA). Cells were maintained as already described [ 80 , 81 ]. RD and RH30 were cultured respectively Dulbecco’s Modified Eagle’s and RPMI medium containing 10% Fetal Calf Serum (Hyclone, Logan, UT, USA) supplemented with glutamine and gentamycin (GIBCO-BRL Gaithersburg, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells

Cassandri

Pomella

Rossetti

et al. 2021

IJMS

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS−275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS−275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS−275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS−275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS−275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.

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“…SNAI2 is highly expressed in FN-RMS, is oncogenic, blocks myogenic differentiation, and promotes growth. MYOD activates SNAI2 transcription via super enhancers with striped 3D contact architecture (Pomella et al, 2021). In vitro functional studies demonstrate that the subtype switch caused by the loss of SOX10 is analogous to the proneural-mesenchymal transition observed in patients at the transcriptomics, epigenetic, and phenotypic levels.…”

Section: Discussionmentioning

confidence: 93%

Construction of a Prognostic Immune-Related LncRNA Risk Model for Lung Adenocarcinoma

Shen

Wang

et al. 2021

Front. Cell Dev. Biol.

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BackgroundLung adenocarcinoma (LUAD) originates mainly from the mucous epithelium and glandular epithelium of the bronchi. It is the most common pathologic subtype of non-small cell lung cancer (NSCLC). At present, there is still a lack of clear criteria to predict the efficacy of immunotherapy. The 5-year survival rate for LUAD patients remains low.MethodsAll data were downloaded from The Cancer Genome Atlas (TCGA) database. We used Gene Set Enrichment Analysis (GSEA) database to obtain immune-related mRNAs. Immune-related lncRNAs were acquired by using the correlation test of the immune-related genes with R version 3.6.3 (Pearson correlation coefficient cor = 0.5, P < 0.05). The TCGA-LUAD dataset was divided into the testing set and the training set randomly. Based on the training set to perform univariate and multivariate Cox regression analyses, we screened prognostic immune-related lncRNAs and given a risk score to each sample. Samples were divided into the high-risk group and the low-risk group according to the median risk score. By the combination of Kaplan–Meier (KM) survival curve, the receiver operating characteristic (ROC) (AUC) curve, the independent risk factor analysis, and the clinical data of the samples, we assessed the accuracy of the risk model. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the differentially expressed mRNAs between the high-risk group and the low-risk group. The differentially expressed genes related to immune response between two risk groups were analyzed to evaluate the role of the model in predicting the efficacy and effects of immunotherapy. In order to explain the internal mechanism of the risk model in predicting the efficacy of immunotherapy, we analyzed the differentially expressed genes related to epithelial-mesenchymal transition (EMT) between two risk groups. We extracted RNA from normal bronchial epithelial cell and LUAD cells and verified the expression level of lncRNAs in the risk model by a quantitative real-time polymerase chain reaction (qRT-PCR) test. We compared our risk model with other published prognostic signatures with data from an independent cohort. We transfected LUAD cell with siRNA-LINC0253. Western blot analysis was performed to observed change of EMT-related marker in protein level.ResultsThrough univariate Cox regression analysis, 24 immune-related lncRNAs were found to be strongly associated with the survival of the TCGA-LUAD dataset. Utilizing multivariate Cox regression analysis, 10 lncRNAs were selected to establish the risk model. The K-M survival curves and the ROC (AUC) curves proved that the risk model has a fine predictive effect. The GO enrichment analysis indicated that the effect of the differentially expressed genes between high-risk and low-risk groups is mainly involved in immune response and intercellular interaction. The KEGG enrichment analysis indicated that the differentially expressed genes between high-risk and low-risk groups are mainly involved in endocytosis and the MAPK signaling pathway. The expression of genes related to the efficacy of immunotherapy was significantly different between the two groups. A qRT-PCR test verified the expression level of lncRNAs in LUAD cells in the risk model. The AUC of ROC of 5 years in the independent validation dataset showed that this model had superior accuracy. Western blot analysis verified the change of EMT-related marker in protein level.ConclusionThe immune lncRNA risk model established by us could better predict the prognosis of patients with LUAD.

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Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma

Cited by 36 publications

References 49 publications

Pioneer factors in development and cancer

Pioneer factors in development and cancer

MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells

Construction of a Prognostic Immune-Related LncRNA Risk Model for Lung Adenocarcinoma

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