METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation.
METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation.
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DOI：
10.1186/s13045-024-01526-9
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发表时间：
2024-02-01
影响因子：
28.5
通讯作者：
中科院分区：
文献类型：
--
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虽然肝癌干细胞（CSC）在肝细胞癌（HCC）的发生、进展、复发和治疗抗性中起着至关重要的作用，但肝脏CSC自我更新的机制仍然难以捉摸。我们的目的是描述甲基转移酶16（Methyltransferase 16，简称L16），一种最近发现的RNA N6-甲基腺苷（m6 A）甲基转移酶，在HCC的发展/维持、CSC干性以及正常肝发生中的作用。产生肝脏特异性Mettl 16条件性KO（cKO）小鼠以评估其在HCC发病机制和正常肝发生中的作用。利用流体动力学尾静脉注射（HDTVi）诱导的原发性肝癌发生和异种移植模型来确定胃L16在HCC起始和进展中的作用。采用有限稀释法评价CSC频率。通过多组学数据的综合分析，包括RNA-seq，RNA免疫沉淀（RIP）-seq和核糖体分析，揭示了功能上重要的靶标。胃L16在肝CSC中高度表达，并且其消耗显著降低体外和体内CSC频率。Mettl 16 KO显著减弱HCC的发生和进展，但仅轻微影响正常肝发生。机制研究，包括高通量测序，揭示了胃L16作为核糖体RNA（rRNA）成熟和mRNA翻译的关键调节因子，并确定了真核翻译起始因子3亚基a（eIF 3a）转录物作为HCC中胃L16的真正靶点。此外，通过CRISPR基因拼接扫描揭示了胃L16的功能性必需区域，这将为开发潜在的抑制剂铺平道路。我们的研究结果强调了胃L16在促进HCC发病机制和通过增加mRNA翻译效率增强肝脏CSC自我更新中的关键致癌作用。在线版本包含补充材料，可通过10.1186/s13045-024-01526-9获得。
While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N6-methyladenosine (m6A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis. Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling. METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s). Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency. The online version contains supplementary material available at 10.1186/s13045-024-01526-9.
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影响因子：
14.9
作者：
Sekiguchi T;Hayano T;Yanagida M;Takahashi N;Nishimoto T
通讯作者：
Nishimoto T
影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
48
作者：
Linder, Bastian;Grozhik, Anya V.;Olarerin-George, Anthony O.;Meydan, Cem;Mason, Christopher E.;Jaffrey, Samie R.
通讯作者：
Jaffrey, Samie R.
人腺苷RNA甲基转移酶和去甲基酶的全面相互作用揭示了不同的功能和调节特征。
影响因子：
14.9
作者：
Covelo-Molares H;Obrdlik A;Poštulková I;Dohnálková M;Gregorová P;Ganji R;Potěšil D;Gawriyski L;Varjosalo M;Vaňáčová Š
通讯作者：
Vaňáčová Š
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE