L3MBTL2 maintains MYCN-amplified neuroblastoma cell proliferation through silencing NRIP3 and BRME1 genes

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-08-27 DOI:10.1111/gtc.13148

Ryu Okada, Hisanori Takenobu, Shunpei Satoh, Ryuichi P. Sugino, Ritsuko Onuki, Masayuki Haruta, Kyosuke Mukae, Atsuko Nakazawa, Jesmin Akter, Miki Ohira, Takehiko Kamijo

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Abstract

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.

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L3MBTL2 通过沉默 NRIP3 和 BRME1 基因维持 MYCN 扩增的神经母细胞瘤细胞增殖。

表观遗传学的改变对肿瘤的发展有着至关重要的影响。多聚胞复合体是一种进化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。多聚胞抑制复合体1（PRC1）复合体1-6（PRC1.1-6）介导组蛋白H2A赖氨酸119上的泛素化（H2AK119ub）。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敲除和敲低显示，L3MBTL2耗竭可通过细胞周期停滞和γ-H2A.X上调抑制NB细胞增殖。L3MBTL2-敲除可显著抑制异种移植肿瘤的形成。转录组分析显示，细胞周期相关通路被抑制，而分化相关通路被激活。L3MBTL2-敲除明显抑制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）。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。回溯研究揭示了L3MBTL2-BRME1和-NRIP3轴对NB细胞增殖的重要性。我们进一步证实了在 L3MBTL2 缺失的情况下，MYCN 与 NRIP3 的去抑制相关。因此，本研究首次揭示了 L3MBTL2 介导的基因沉默在 MYCN 扩增的 NB 细胞中的意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.