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N1-methyladenosine methylations in tRNA drive liver tumorigenesis by PPARδ-mediated cholesterol synthesis

ABSTRACT: Increased protein translation plays a critical role in cancer development and treatment1,2. However, the molecular mechanism that is involved in this process remains poorly understood. N1-methyladenosine (m1A) methylation in RNA accounts for regulating mRNA translation in a post-transcriptional manner3,4. Here we show that m1A methylation levels are remarkably elevated in hepatocellular carcinoma (HCC) patient tumor tissues, especially in patients with microscopic vascular invasion (MVI). Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. Consistently, TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumors and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylations are required for self-renewal of liver CSCs and tumorigenesis. Mechanistically, TRMT6/TRMT61A-dependent m1A in tRNA boost PPARδ expression, which triggers cholesterol synthesis to activate Hedgehog signaling, driving self-renewal of liver CSCs and tumorigenesis. For potential therapeutic benefit, we further identify a specific inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer with high m1A methylations. Our findings provide novel insights into the function and molecular mechanism of m1A modifications underlying liver tumorigenesis and drug target, which will serve as a new biomarker for HCC and pave a new way to develop more effective therapeutic strategies for HCC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147840 | GEO | 2021/03/01

REPOSITORIES: GEO

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Project description:Following synthesis, RNA can be modified with over 100 chemically distinct modifications, and in recent years it was shown that processing, localization, stability and translation of mRNAs can be impacted by an increasing number of these modifications. An emerging modification, present across all three domains of life, is N1-methyladenosine (m1A). m1A is of particular interest, as its methyl group disrupts Watson-Crick base pairing and it thus harbors substantial regulatory potential. Recent studies have suggested this modification to be relatively common in mammalian mRNA, but lacked the resolution of identifying individual m1A containing bases, and did not identify specific sequence motifs required for their modification or the enzymatic machinery catalyzing them. This rendered it challenging to validate the putative substrates and to address their function and mechanisms of action. Here we develop a highly sensitive and specific approach allowing the semi-quantitative mapping of m1A at single nucleotide resolution and in a transcriptome-wide manner. We found m1A to be present in cytosolic and mitochondrial mRNAs. In the cytosol m1A is present in a low number of mRNAs, typically at very low stoichiometry, almost invariably in the loop of hairpin structures, where it is introduced by the TRMT6/TRMT61A complex. In contrast, we found a single site in the mitochondrial ND5 mRNA, catalyzed by TRMT10C, with tightly regulated methylation levels in human development, ranging from nearly 100% up to the 8-cell stage and down to ~20% at the late blastocyst stage. We find that methylation at this site is the hallmark of hyper-stable transcripts, which are maternally transmitted and persist until the onset of zygotic mitochondrial transcription. Finally, we found that polysomes are strongly depleted from methylated mRNAs and that reporters harboring m1A in regions encountered by ribosomes (5’ UTR and CDS), but not in 3’ UTRs, are translated at reduced rates. Our findings suggest that m1A on mRNA, likely due to its dramatic impact on base pairing, lead to repression of translation which is by and large avoided by cells, while revealing one case - in mitochondria - where tight spatiotemporal control over m1A levels was adopted by cells as a potential means of post-transcriptional regulation.

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N1-methyladenosine methylations in tRNA drive liver tumorigenesis by PPARδ-mediated cholesterol synthesis

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