Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future. 

/pdf/m6a-modification-recent-advances-anticancer-targeted-drug-2og6181j.pdf

m6A modification: recent advances, anticancer targeted drug discovery and beyond

Eliminating METTL1‐mediated accumulation of PMN‐MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation

Abstract The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 protein (WDR4), the two key components of the tRNA N7-methylguanosine (m7G) methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance. Significance: Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance. 

METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma

RNA-binding Proteins and Cancer Metastasis.

BACKGROUND & AIMS
RNA N6-Methyladenosine (m6A) reader protein YTHDF1 has been implicated in cancer; however, its role in hepatocellular carcinoma (HCC), especially in nonalcoholic steatohepatitis-associated HCC (NASH-HCC), remains unknown. Here, we investigated the functional role and molecular mechanism of YTHDF1 on NASH-HCC and its interplay with tumor immune microenvironment.


METHODS
Hepatocyte specific Ythdf1 overexpression mice was subjected to dietary models of NASH-HCC. Tumor infiltrating immune cells were profiled with single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunostaining. The molecular target of YTHDF1 was elucidated with RNA-sequencing, m6A-sequencing, YTHDF1 RNA immunoprecipitation (RIP) sequencing, proteomics, and ribosome-profiling. Ythdf1 in NASH-HCC models was targeted by lipid nanoparticles (LNP)-encapsulated siYthdf1.


RESULTS
YTHDF1 is overexpressed in tumor tissues than adjacent peri-tumor tissues from NASH-HCC patients. Liver specific Ythdf1 overex pression drives tumorigenesis in dietary models of spontaneous NASH-HCC. scRNA-seq and flow cytometry unraveled that Ythdf1 induced accumulation of myeloid-derived suppressor cells (MDSCs) and suppressed cytotoxic CD8+ T cell function. Mechanistically, Ythdf1 expression in NASH-HCC cells induced the secretion of IL-6, which mediated MDSCs recruitment and activation, leading to CD8+ T cell dysfunction. Integrated m6A-seq, RIP-seq, and ribo-seq have identified EZH2 mRNA as a key YTHDF1 target. YTHDF1 binds to m6A-modified EZH2 mRNA and promotes EZH2 translation. EZH2 in turn increased expression and secretion of IL-6. Ythdf1 knockout synergized with anti-PD-1 treatment to suppress tumor growth in NASH-HCC allografts. Furthermore, therapeutic targeting of Ythdf1 using LNP encapsulated siRNA significantly increased efficacy of anti-PD-1 blockade in NASH-HCC allografts.


CONCLUSIONS
We identified that YTHDF1 promotes NASH-HCC tumorigenesis via EZH2-IL-6 signaling, which recruits and activates MDSCs to cause cytotoxic CD8+ T cell dysfunction. YTHDF1 may be a novel therapeutic target to improve response to anti-PD-1 immunotherapy for NASH-HCC.

Targeting N6-methyladenosine reader YTHDF1 with siRNA boosts anti-tumor immunity in NASH-HCC by inhibiting EZH2-IL-6 axis.

Insufficient Radiofrequency Ablation Promotes Hepatocellular Carcinoma Metastasis Through N6-Methyladenosine mRNA Methylation-Dependent Mechanism

METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance

A kink-turn (K-turn) is a three-dimensional RNA structure that exists in all three primary phylogenetic domains. In this study, we developed the RIP-PEN-seq method to identify the full-length sequences of RNAs bound by the K-turn binding protein 15.5K and discovered a previously uncharacterized class of RNAs with backward K-turn motifs (bktRNAs) in humans and mice. All bktRNAs share two consensus sequence motifs at their fixed terminal position and have complex folding properties, expression and evolution patterns. We found that a highly conserved bktRNA1 guides the methyltransferase fibrillarin to install RNA methylation of U12 small nuclear RNA in humans. Depletion of bktRNA1 causes global splicing dysregulation of U12-type introns by impairing the recruitment of ZCRB1 to the minor spliceosome. Most bktRNAs regulate the splicing of local introns by interacting with the 15.5K protein. Taken together, our findings characterize a class of small RNAs and uncover another layer of gene expression regulation that involves crosstalk among bktRNAs, RNA splicing and RNA methylation. Immunoprecipitation coupled with paired-end sequencing of non-coding RNAs identifies a class of splicing regulators. 

/pdf/rip-pen-seq-identifies-a-class-of-kink-turn-rnas-as-splicing-3akppu4h.pdf

RIP-PEN-seq identifies a class of kink-turn RNAs as splicing regulators

Although the function of tRNA in translational process is well established, it remains controversial whether tRNA abundance is tightly associated with translational efficiency (TE) in mammals. For example, how critically the expression of tRNAs contributes to the establishment of tissue-specific proteomes in mammals has not been well addressed. Here, we measured both tRNA expression using DM-tRNA-seq and ribosome-associated mRNAs in the brain, heart, and testis of RiboTag mice. Remarkable variation in the expression of tRNA isodecoders was observed among the different tissues. When the statistical effect of isodecoder-grouping on reducing variations is considered through permutating the anticodons, we observed an expected reduction in the tissue-variations of anticodon expression, an unexpected smaller variation of anticodon usage bias, and an unexpected larger variation of tRNA isotype expression. Regardless whether or not they share the same anticodons, isotypes encoding the same amino acids are co-expressed across different tissues. Based on the tRNA expression and TE computed from RiboTag-seq, we find that the tRNA adaptation index (tAI) values and TE are significantly correlated in the same tissues but not among tissues; tRNAs and the amino acid compositions of translating peptides are positively correlated in the same tissues but not between tissues. We therefore hypothesize that the tissue-specific expression of tRNAs might be related to post-transcriptional mechanisms, such as aminoacylation, modification, and tRNA-derived small RNAs (tsRNAs). This study provides a resource for tRNA and translation studies to gain novel insights into the dynamics of tRNAs and their role in translational regulation.

Dynamic Landscapes of tRNA Transcriptomes and Translatomes in Diverse Mouse Tissues

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Insufficient Radiofrequency Ablation Promotes Hepatocellular Carcinoma Metastasis Through N6-Methyladenosine mRNA Methylation-Dependent Mechanism

METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance

RIP-PEN-seq identifies a class of kink-turn RNAs as splicing regulators

Dynamic Landscapes of tRNA Transcriptomes and Translatomes in Diverse Mouse Tissues