Abstract
C19MC is part of an oncogenic circuit that drives embryonal brain tumors with multilayered rosettes.
Major Finding: C19MC is part of an oncogenic circuit that drives embryonal brain tumors with multilayered rosettes.
Concept: TTYH1–C19MC- and MYCN-associated superenhancers enhance a C19MC–LIN28A–MYCN feed-forward loop.
Impact: Inhibiting bromodomains may be a potential therapeutic strategy for patients with ETMRs.
Embryonal brain tumors with multilayered rosettes (ETMR), aggressive malignancies that arise in infants and young children, have a long-term survival rate of only 10% to 20% and tend to progress rapidly. ETMRs are characterized by recurrent amplification of C19MC (a primate-specific miRNA cluster on Chr19q13.41) and fusion of Tweety homolog 1 (TTYH1) with C19MC, and exhibit upregulation of the pluripotency factor and RNA-binding protein LIN28A. To ascertain the biological relevance of C19MC amplifications in ETMRs, Sin-Chan, Mumal, and colleagues transduced the hNSC cell line and a cell line derived from a primary ETMR with 5 C19MC miRNAs (5miR). Expression of 5miR promoted increased proliferation of both cell lines and led to upregulation of the oncoproteins LIN28A and MYCN in hNSC cells and inhibition of expression of the mRNA decay–associated protein Tristetraprolin (TTP). LIN28A was shown to negatively regulate TTP and positively regulate MYCN in ETMRs, suggesting that a C19MC–LIN28A–MYCN circuit drives ETMR, and regulate the expression of epigenetic modifiers. Integrated transcriptomic and epigenomic analyses showed that a hybrid TTYH1–C19MC superenhancer and long-range MYCN-enhancer interactions occurred specifically in ETMRs and fetal NSCs. Consistent with these findings, processes regulated by MYCN and its binding partner MAZ were upregulated in primary ETMRs, suggesting ETMRs may be susceptible to certain bromodomain inhibitors. Supporting this idea, the bromodomain inhibitor JQ1S reduced viability of cells derived from a primary ETMR transduced with 5miR and resulted in downregulation of MYCN, MAZ, LIN28A, DNMT3B6/A2, and BRD2; further, JQ1S reduced expression of endogenous C19MC, LIN28A, and DNMTB6 in ETMR cells. Together, these findings provide mechanistic insight into the pathogenesis of ETMR and suggest a therapeutic avenue worth exploring for this little-understood type of cancer.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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