L3MBTL2 maintains <i>MYCN</i>‐amplified neuroblastoma cell proliferation through silencing <i>NRIP3</i> and <i>BRME1</i> genes

<jats:title>Abstract</jats:title><jats:p>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. <jats:italic>L3MBTL2</jats:italic>‐knockout and knockdown revealed that L3MBTL2 depletion suppressed NB cell proliferation via cell‐cycle arrest and gamma‐H2A.X upregulation. <jats:italic>L3MBTL2‐</jats:italic>knockout profoundly suppressed xenograft tumor formation. Transcriptome analysis revealed suppressed cell‐cycle‐related and activated differentiation‐related pathways. <jats:italic>Break repair meiotic recombinase recruitment factor 1</jats:italic> (<jats:italic>BRME1</jats:italic>) and <jats:italic>nuclear receptor interacting protein 3</jats:italic> (<jats:italic>NRIP3</jats:italic>) were notably de‐repressed by <jats:italic>L3MBTL2</jats:italic>‐knockout. The deletion of <jats:italic>L3MBTL2</jats:italic> 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 <jats:italic>NRIP3</jats:italic> in an <jats:italic>L3MBTL2</jats:italic>‐deficient context. Therefore, this study first revealed the significance of <jats:italic>L3MBTL2‐</jats:italic>mediated gene silencing in MYCN‐amplified NB cells.</jats:p>