表观遗传改变严重影响肿瘤的发展。多梳群复合物构成了一种进化上保守的表观遗传机制，可调节干细胞的命运和发育​​。它们主要通过组蛋白修饰参与肿瘤发生。 Polycomb 抑制复合物 1 (PRC1) 复合物 1-6 (PRC1.1-6) 介导组蛋白 H2A 在赖氨酸 119 (H2AK119ub) 上的泛素化。在这里，我们研究了 PRC1.6 分子 L3MBTL2 在神经母细胞瘤 (NB) 细胞中的功能作用。 L3MBTL2 敲除和敲低表明 L3MBTL2 耗竭通过细胞周期停滞和 γ-H2A.X 上调抑制 NB 细胞增殖。 L3MBTL2 敲除显着抑制了异种移植肿瘤的形成。转录组分析显示细胞周期相关途径受到抑制，分化相关途径被激活。 L3MBTL2 敲除显着降低了断裂修复减数分裂重组酶招募因子 1 (BRME1) 和核受体相互作用蛋白 3 (NRIP3) 的抑制。 L3MBTL2 的缺失减少了 H2AK119ub 和 PCGF6 在靶标转录起始位点近端区域的富集。回加研究揭示了 L3MBTL2-BRME1 和 -NRIP3 轴对 NB 细胞增殖的重要性。我们进一步证明了在 L3MBTL2 缺陷的情况下 MYCN 与 NRIP3 去抑制的关联。因此，本研究首次揭示了 MYCN 扩增的 NB 细胞中 L3MBTL2 介导的基因沉默的意义。© 2024 日本分子生物学会和 John Wiley

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.© 2024 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.