A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Sin‐Chan, Patrick; Mumal, Iqra; Suwal, Tannu; Ho, Ben; Fan, Xiaolian; Singh, Irtisha; Du, Yuchen; Lu, Mi; Patel, Neilket; Torchia, Jonathon; Popovski, Dean; Fouladi, Maryam; Guilhamon, Paul; Hansford, Jordan R.; Leary, Sarah; Hoffman, Lindsey M.; Levy, Jean M. Mulcahy; Lassaletta, Álvaro; Solano-Páez, Palma; Rivas, Eloy; Reddy, Alyssa; Gillespie, G. Yancey; Gupta, Nalin; Meter, Timothy E. Van; Nakamura, Hideo; Wong, Tai-Tong; Shin, Young; Kim, Seung Ki; Massimi, Luca; Grundy, Richard G.; Fangusaro, Jason; Johnston, Donna L.; Chan, Jennifer A.; Lafay‐Cousin, Lucie; Hwang, Eui-Hyoung; Wang, Yin; Catchpoole, Daniel; Michaud, Jean; Ellezam, Benjamin; Ramanujachar, Ramya; Lindsay, Holly; Taylor, Michael D.; Hawkins, Cynthia; Bouffet, Éric; Jabado, Nada; Singh, Sheila K.; Kleinman, Claudia L.; Baršytė-Lovejoy, Dalia; Li, Xiao Nan; Dirks, Peter B.; Lin, Charles Y.; Mack, Stephen C.; Rich, Jeremy; Huang, Annie

doi:10.1016/j.ccell.2019.06.002

Cited by 74 publications

(55 citation statements)

References 74 publications

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“…ETMRs are characterized by the amplification of C19MC. High expression levels of C19MC, LIN28A, and MYCN comprise an oncogenic circuit in this tumor type [177]. This oncogenic circuit is reinforced by an enhancer hijacking mechanism: the formation of hybrid SEs via C19MC-TTYH1 gene fusion, which juxtaposes TTYH1-associated SEs and C19MC-associated enhancers located in distinct loci of chromosome 19.…”

Section: Super-enhancer-associated Mirnas In Diseasementioning

confidence: 99%

“…In addition, miRNAs with SE gain were associated with a worse prognosis. A recent report described the relationship between the Chr19q13.41 miRNA cluster (C19MC), encoding 54 miRNAs normally expressed in placental and germinal tissues, and SEs in highly lethal type of infant brain cancer, embryonal tumors with multilayered rosettes (ETMRs) [177]. ETMRs are characterized by the amplification of C19MC.…”

Section: Super-enhancer-associated Mirnas In Diseasementioning

confidence: 99%

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Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Matsuyama

Suzuki

2019

IJMS

194

141

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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA–target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases.

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Section: Super-enhancer-associated Mirnas In Diseasementioning

confidence: 99%

Section: Super-enhancer-associated Mirnas In Diseasementioning

confidence: 99%

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Matsuyama

Suzuki

2019

IJMS

194

141

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“…LIN28A regulates epigenetic effecters to promote cell growth, survival, and tumor development. C19MC drives tumor cell growth through MYCN-mediated transcriptional regulator circuity, which also shows therapeutic vulnerability [170]. Moreover, C19MC amplification changes DNA methylation by elevating DNMT3b expression, which promotes cell pluripotency and indicates poor prognosis [171,172].…”

Section: The Roles Of Mirna Clusters In Csc Pathogenesismentioning

confidence: 99%

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

Jiao

Qian

et al. 2019

Cells

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Cancer ranks as the second leading cause of death worldwide, causing a large social and economic burden. However, most anti-cancer treatments face the problems of tumor recurrence and metastasis. Therefore, finding an effective cure for cancer needs to be solved urgently. Recently, the discovery of cancer stem cells (CSCs) provides a new orientation for cancer research and therapy. CSCs share main characteristics with stem cells and are able to generate an entire tumor. Besides, CSCs usually escape from current anti-cancer therapies, which is partly responsible for tumor recurrence and poor prognosis. microRNAs (miRNAs) belong to small noncoding RNA and regulate gene post-transcriptional expression. The dysregulation of miRNAs leads to plenty of diseases, including cancer. The aberrant miRNA expression in CSCs enhances stemness maintenance. In this review, we summarize the role of miRNAs on CSCs in the eight most common cancers, hoping to bridge the research of miRNAs and CSCs with clinical applications. We found that miRNAs can act as tumor promoter or suppressor. The dysregulation of miRNAs enhances cell stemness and contributes to tumor metastasis and therapeutic resistance via the formation of feedback loops and constitutive activation of carcinogenic signaling pathways. More importantly, some miRNAs may be potential targets for diagnosis, prognosis, and cancer treatments.

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“…These extended regions, also called stretch enhancers, clusters of regulatory elements, or transcriptional locus control regions, mark important genomic loci that are commonly associated with highly transcribed genes that govern cell identity, and oncogenes in cancer [29]. In the context of brain tumours, SE genes have been described across a large set of brain tumour histologies, shown to regulate tumour oncogenes, and represent potential cancer cell vulnerabilities [7,30-32].…”

Section: Enhancers and Gene Transcriptionmentioning

confidence: 99%

“…Additionally, embryonal tumours with multilayered rosettes are characterized by a chromosome 19 miRNA cluster (C19MC) amplification and fusion with the TTYH1 gene locus. This drives C19MC expression using the active regulatory elements of TTYH1 , which is highly expressed during brain development [32]. SEs are amplified in a variety of cancers, albeit at a much lower frequency than gene‐centric alterations [7].…”

Section: Disruption Of Noncoding Elements and Enhancers In Brain Cancermentioning

confidence: 99%

Invited Review: The role and contribution of transcriptional enhancers in brain cancer

Arabzade

Stuckert

Bertrand

et al. 2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 48-56 The role and contribution of transcriptional enhancers in brain cancer Genetic alterations identified across several paediatric and adult brain tumours reveal recurrent disruption of active chromatin landscapes and dysregulation of transcriptional programmes. Noncoding elements, specifically enhancers, are central to these mechanisms, and are influenced by developmental and neural gene regulatory signatures. Epigenomic and transcriptomic methods and techniques have facilitated detection of active enhancers, and characterization of brain tumours integrated with genomic structural information. These datasets have provided new insights into the mechanisms of transcriptional control that are profoundly altered in childhood and adult brain cancer; offering new ideas and molecular targets for therapeutic intervention. This review summarizes recent advances in our understanding of active transcriptional programmes of brain cancer, their impact on tumour development, and research areas for further exploration.

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A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Cited by 74 publications

References 74 publications

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

Invited Review: The role and contribution of transcriptional enhancers in brain cancer

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