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Epigenetic alterations critically affect tumor development. Polycomb‐group complexes constitute an evolutionarily conserved epigenetic machinery that regulates stem cell fate and development. They are implicated in tumorigenesis, primarily via histone modification. Polycomb repressive complex 1 (PRC1) complexes 1–6 (PRC1.1–6) mediate the ubiquitination of histone H2A on lysine 119 (H2AK119ub). Here, we studied the functional roles of a PRC1.6 molecule, L3MBTL2, in neuroblastoma (NB) cells. L3MBTL2‐knockout and knockdown revealed that L3MBTL2 depletion suppressed NB cell proliferation via cell‐cycle arrest and gamma‐H2A.X upregulation. L3MBTL2‐knockout profoundly suppressed xenograft tumor formation. Transcriptome analysis revealed suppressed cell‐cycle‐related and activated differentiation‐related pathways. Break repair meiotic recombinase recruitment factor 1 (BRME1) and nuclear receptor interacting protein 3 (NRIP3) were notably de‐repressed by L3MBTL2‐knockout. The deletion of L3MBTL2 reduced enrichment of H2AK119ub and PCGF6 at transcriptional start site proximal regions of the targets. Add‐back studies unveiled the importance of L3MBTL2‐BRME1 and ‐NRIP3 axes for NB cell proliferation. We further manifested the association of MYCN with de‐repression of NRIP3 in an L3MBTL2‐deficient context. Therefore, this study first revealed the significance of L3MBTL2‐mediated gene silencing in MYCN‐amplified NB cells. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell‐ or osteoblast‐derived osteosarcoma is the most common malignant bone tumor. Its highly metastatic malignant phenotypes, which are often associated with a poor prognosis, have been correlated with the modulation of TP53‐ and cell‐cycle‐related pathways. MYC, which regulates the transcription of cell‐cycle modulating genes, is used as a representative prognostic marker for osteosarcoma. Another member of the MYC oncoprotein family, MYCN, is highly expressed in a subset of osteosarcoma, however its roles in osteosarcoma have not been fully elucidated. Here, we attempted to create an in vitro tumorigenesis model using hiPSC‐derived neural crest cells, which are precursors of mesenchymal stem cells, by overexpressing MYCN on a heterozygous TP53 hotspot mutation (c.733G>A; p.G245S) background. MYCN‐expressing TP53 mutated transformed clones were isolated by soft agar colony formation, and administered subcutaneously into the periadrenal adipose tissue of immunodeficient mice, resulting in the development of chondroblastic osteosarcoma. MYCN suppression decreased the proliferation of MYCN‐induced osteosarcoma cells, suggesting MYCN as a potential target for a subset of osteosarcoma treatment. Further, comprehensive analysis of gene expression and exome sequencing of MYCN‐induced clones indicated osteosarcoma‐specific molecular features, such as the activation of TGF‐β signaling and DNA copy number amplification of GLI1. The model of MYCN‐expressing chondroblastic osteosarcoma was developed from hiPSC‐derived neural crest cells, providing a useful tool for the development of new tumor models using hiPSC‐derived progenitor cells with gene modifications and in vitro transformation. [ABSTRACT FROM AUTHOR]