Failure to downregulate the BAF53a subunit of the SWI/SNF chromatin remodeling complex contributes to the differentiation block in rhabdomyosarcoma

Taulli, Riccardo; Foglizzo, Valentina; Morena, Deborah; Dm, Coda; Ala, Ugo; Bersani, Francesca; Maestro, Nicola; Ponzetto, Carola

doi:10.1038/onc.2013.188

Cited by 46 publications

(46 citation statements)

References 45 publications

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“…[302] p57, Bax and caspase-3 miR-206 is a potent tumor supressor p57 and Bax upregulated, and cleaved caspase-3 protein upregulated ACI model rat mammary tissue [308] Actin-like 6A (BAF53a), a subunit of the SWI/SNF chromatin remodeling complex Elevated BAF53a Downregulation of miR-206 Primary rhabdomyosarcoma tumors [309] Actin-like 6A (BAF53a) BAF53a transcript is significantly higher in primary rhabdomyosarcomas than in normal muscle…”

Section: Myomirs and Cancermentioning

confidence: 99%

“…Restoration of miR-206 expression downregulated BAF53a, which inhibits proliferation and anchorage independent growth; Primary rhabdomyosarcoma tumors [309] BAF53a and is a direct target of miR-206 the abundance of factors involved in aspects of cell proliferation [84] . Some cancers however show that elevation of myomiR levels promotes cancer progression (Figure 3), indicating that in such cell environments the deregulated myomiR is oncogenic and their targets here are normal tumorsuppressor cell factors.…”

Section: Myomirs and Cancermentioning

confidence: 99%

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Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Mitchelson¹

2015

WJBC

140

132

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MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/ tissue regeneration/tissue inflammation responses, and cancer development. Core tip: The roles of the canonical muscle-associated microRNAs are reviewed, including microRNA families miR-1 and miR-133, and single miR-206, which are collectively known as the "myomiRs". The myomiRs act at the crossroads of the molecular regulation of muscle cells, linking between pathways for cell differentiation, development and maintenance, but also potentiate aberrant cell growth in numerous non-muscle cancers. Typically myomiRs are downregulated in cancers, but some myomiRs are upregulated in a few cancers, yet each dysregulation event advances tumor progression. The review examines normal and disease-linked molecular changes associated with the myomiRs, and collates the extensive literature into accessible tables. REVIEW

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Section: Myomirs and Cancermentioning

confidence: 99%

Section: Myomirs and Cancermentioning

confidence: 99%

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Mitchelson¹

2015

WJBC

140

132

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“…9,24 Cells were grown in DMEM (Euroclone) supplemented with 10% FBS (Euroclone). To obtain differentiation of C2C12 myoblast into myotubes, cells were plated at subconfluence, kept in growth medium for 24 hours, and then switched to differentiation medium (DMEM containing 2% HS).…”

Section: Reagentsmentioning

confidence: 99%

“…12 This tilts the balance toward active MyoD, which further enhances miR-206 transcription. Besides freeing MyoD from its inhibitory partners, miR-206 cooperates with the MRFs by contributing to the block of proliferation via direct downregulation of targets such as Pola1, 5 Cyclin D1 13,14 and Cyclin D2, 15 Met, 9,16 Pax3, 15,17 Pax7, 18 YY1, 19 HDAC4, 20,21 Snail, 22 Notch3, 23 and BAF53a, 24 and by indirectly reactivating differentiation genes. In this work, in the effort of identifying new effectors of miR-206 critical for its differentiation-promoting activity, we focused on 2 genes emerged from the original global expression analysis of miR-206-converted RMS cells.…”

Section: Introductionmentioning

confidence: 99%

SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma

et al. 2015

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Rhadomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. RMS cells resemble fetal myoblasts but are unable to complete myogenic differentiation. In previous work we showed that miR-206, which is low in RMS, when induced in RMS cells promotes the resumption of differentiation by modulating more than 700 genes. To better define the pathways involved in the conversion of RMS cells into their differentiated counterpart, we focused on 2 miR-206 effectors emerged from the microarray analysis, SMYD1 and G6PD. SMYD1, one of the most highly upregulated genes, is a H3K4 histone methyltransferase. Here we show that SMYD1 silencing does not interfere with the proliferative block or with the loss anchorage independence imposed by miR-206, but severely impairs differentiation of ERMS, ARMS, and myogenic cells. Thus SMYD1 is essential for the activation of muscle genes. Conversely, among the downregulated genes, we found G6PD, the enzyme catalyzing the rate-limiting step of the pentose phosphate shunt. In this work, we confirmed that G6PD is a direct target of miR-206. Moreover, we showed that G6PD silencing in ERMS cells impairs proliferation and soft agar growth. However, G6PD overexpression does not interfere with the prodifferentiating effect of miR-206, suggesting that G6PD downmodulation contributes to -but is not an absolute requirement for -the tumor suppressive potential of miR-206. Targeting cancer metabolism may enhance differentiation. However, therapeutic inhibition of G6PD is encumbered by side effects. As an alternative, we used DCA in combination with miR-206 to increase the flux of pyruvate into the mitochondrion by reactivating PDH. DCA enhanced the inhibition of RMS cell growth induced by miR-206, and sustained it upon miR-206 de-induction. Altogether these results link miR-206 to epigenetic and metabolic reprogramming, and suggest that it may be worth combining differentiation-inducing with metabolism-directed approaches.

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“…This could indicate an abundance of a neural progenitor form of the SWI/SNF complex as opposed to the SWI/SNF found in differentiated neurons [27]. ACTL6A overexpression has been linked to an undifferentiated state in tumors such as rhabdomyosarcoma [28]. Overall, the most significantly affected pathways were cyclins and cyclindependent kinases, growth factor receptors such as EGFR and FGFR, and chromatin regulators such as HDACs and SMARCB1.…”

Section: A Look Into Genomics Of Rhabdoid Tumors and Comparison With mentioning

confidence: 99%

Diagnostic Value of Next-Generation Sequencing in an Unusual Sphenoid Tumor

Jamshidi

Pleasance

et al. 2014

The Oncologist

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Extraordinary advancements in sequencing technology have made what was once a decade-long multi-institutional endeavor into a methodology with the potential for practical use in a clinical setting.We therefore set out to examine the clinical value of next-generation sequencing by enrolling patients with incurable or ambiguous tumors into the Personalized OncoGenomics initiative at the British Columbia Cancer Agency whereby whole genome and transcriptome analyses of tumor/ normal tissue pairs are completed with the ultimate goal of directing therapeutics. First, we established that the sequencing, analysis, and communication with oncologists could be completed in less than 5 weeks. Second, we found that cancer diagnostics is an area that can greatly benefit from the comprehensiveness of a whole genome analysis. Here, we present a scenario in which a metastasized sphenoid mass, which was initially thought of as an undifferentiated squamous cell carcinoma, was rediagnosed as an SMARCB1-negative rhabdoid tumor based on the newly acquired finding of homozygous SMARCB1 deletion. The new diagnosis led to a change in chemotherapy and a complete nodal response in the patient. This study also provides additional insight into the mutational landscapeof an adult SMARCB1-negative tumor that has not been explored at a whole genome and transcriptome level. The Oncologist 2014;19:623-630Implications for Practice: We show that use of next-generation sequencing in clinical settings is practical and can benefit patients because of the ability to define tumors genetically.

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Failure to downregulate the BAF53a subunit of the SWI/SNF chromatin remodeling complex contributes to the differentiation block in rhabdomyosarcoma

Cited by 46 publications

References 45 publications

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma

Diagnostic Value of Next-Generation Sequencing in an Unusual Sphenoid Tumor

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