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| 1 | Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma显示文摘Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients. | Demeng Chen Zhiqiang Zhao Zixin Huang Du-Chu Chen Xin-Xing Zhu Yi-Ze Wang Ya-Wei Yan Shaojun Tang Subha Madhavan Weiyi Ni Zhan-peng Huang Wen Li Weidong Ji Huangxuan Shen Shuibin Lin Yi-Zhou Jiang | 2018 | Bone Research2018，6，2： | 5 |
| 2 | A novel inhibitor of N^(6)-methyladenosine demethylase FTO induces m RNA methylation and shows anti-cancer activities显示文摘N^(6)-methyladenosine(m^(6)A)modification is critical for m RNA splicing,nuclear export,stability and translation.Fat mass and obesity-associated protein(FTO),the first identified m^(6)A demethylase,is critical for cancer progression.Herein,we developed small-molecule inhibitors of FTO by virtual screening,structural optimization,and bioassay.As a result,two FTO inhibitors namely 18077 and 18097 were identified,which can selectively inhibit demethylase activity of FTO.Specifically,18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells.In addition,18097 reprogrammed the epi-transcriptome of breast cancer cells,particularly for genes related to P53 pathway.18097 increased the abundance of m^(6)A modification of suppressor of cytokine signaling1(SOCS1)m RNA,which recruited IGF2 BP1 to increase m RNA stability of SOCS1 and subsequently activated the P53 signaling pathway.Further,18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma(PPARγ),CCAAT/enhancer-binding protein alpha(C/EBPa),and C/EBPβ.Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells.Collectively,we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer. | Guoyou Xie Xu-Nian Wu Yuyi Ling Yalan Rui Deyan Wu Jiawang Zhou Jiexin Li Shuibin Lin Qin Peng Zigang Li Hongsheng Wang Hai-Bin Luo | 2022 | Acta Pharmaceutica Sinica B2022，12，2： | 4 |
| 3 | Dynamic Landscapes of tRNA Transcriptomes and Translatomes in Diverse Mouse Tissues显示文摘Although the function of tRNAs in the translational process is well established,it remains controversial whether tRNA abundance is tightly associated with translational efficiency(TE)in mammals.Moreover,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 demethylase-tRNA sequencing(DM-tRNA-seq)and TE of mRNAs using ribosome-tagging sequencing(RiboTag-seq)in the brain,heart,and testis of mice.Remarkable variation in the expression of tRNA isodecoders was observed among 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 variation of anticodon expression across all samples,an unexpected smaller variation of anticodon usage bias,and an unexpected larger variation of tRNA isotype expression at amino acid level.Regardless of whether or not they share the same anticodons,the isodecoders encoding the same amino acids are co-expressed across different tissues.Based on the expression of tRNAs and the TE of mRNAs,we find that the tRNA adaptation index(tAI)and TE are significantly correlated in the same tissues but not between tissues;and tRNA expression and the amino acid composition 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 due to post-transcriptional mechanisms.This study provides a resource for tRNA and translation studies,as well as novel insights into the dynamics of tRNAs and their roles in translational regulation. | Peng Yu Siting Zhou Yan Gao Yu Liang Wenbing Guo Dan Ohtan Wang Shuaiwen Ding Shuibin Lin Jinkai Wang Yixian Cun | 2023 | Genomics, Proteomics & Bioinformatics2023，21，4： | 1 |
| 4 | Emerging functions of tRNA modifications in mRNA translation and diseases显示文摘tRNAs are essential modulators that recognize mRNA codons and bridge amino acids for mRNA translation.The tRNAs are heavily modified,which are essential for forming a complex secondary structure that facilitates codon recognition and mRNA translation.In recent years,studies have identified the regulatory roles of tRNA modifications in mRNA translation networks.Misregulation of tRNA modifications is closely related to the progression of developmental diseases and cancers.In this review,we summarize the tRNA biogenesis process and then discuss the effects and mechanisms of tRNA modifications on tRNA processing and mRNA translation.Finally,we provide a comprehensive overview of the physiological and pathological functions of tRNA modifications,focusing on diseases including cancers. | Lu Wang Shuibin Lin | 2023 | Journal of Genetics and Genomics2023，50，4： | 0 |
| 5 | Mettl5 mediated 18S rRNA N6-methyladenosine(m^(6)A)modification controls stem cell fate determination and neural function显示文摘Ribosome RNA(rRNA)accounts for more than 80%of the cell's total RNA,while the physiological functions of rRNA modifications are poorly understood.Mutations of 18S rRNA m6A methyltransferase METTL5 cause intellectual disability,microcephaly,and facial dysmorphisms in patients,however,little is known about the underlying mechanisms.In this study,we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins.Functionally,we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development.Moreover,using Mettl5 knockout mouse model,we further demonstrated that Mettl5 knockout mice exhibit intellectual disability,recapitulating the human phenotype.Mechanistically,we found that Mettl5 maintains brain function and intelligence by regulating the myelination process.Our study uncovered the causal correlation between mis-regulated 18S rRNA m6A modification and neural function defects,supporting the important physiological functions of rRNA modifications in human diseases. | Lu Wang Yu Liang Rongzhi Lin Qiuchan Xiong Peng Yu Jieyi Ma Maosheng Cheng Hui Han Xiaochen Wang Ganping Wang Fengyin Liang Zhong Pei Demeng Chen Quan Yuan Yi-Zhou Jiang Shuibin Lin | 2022 | Genes & Diseases2022，9，1： | 0 |
| 6 | N^(6)-methyladenosine(m^(6)A)RNA modification in tumor immunity显示文摘Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition.N^(6)-methyladenosine(m^(6)A)modification,the most prevalent epigenetic modification of mammalian mRNAs,has essential functions in regulating the processing and metabolism of its targeted RNAs,and therefore affects various biological processes including tumorigenesis and progression.Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m^(6)A modification in the regulation of tumor immunity.In this review,we summarize recent research progress in the potential roles of m^(6)A modification in tumor immunoregulation,with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways.Furthermore,we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape,and we discuss the prognostic value and therapeutic efficacy of m^(6)A regulators in a variety of cancer types. | Siyi Zheng Hui Han Shuibin Lin | 2022 | Cancer Biology & Medicine2022，19，4： | 0 |
| 7 | Ionizable polymeric nanocarriers for the codelivery of bi-adjuvant and neoantigens in combination tumor immunotherapy显示文摘Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy. | Ting Su Xiang Liu Shuibin Lin Furong Cheng Guizhi Zhu | 2023 | Bioactive Materials2023，，8： | 0 |
| 8 | METTL5 regulates cranial suture fusion via Wnt signaling显示文摘METTL5 is a methyltransferase that mediates eukaryotic 18S ribosomal RNA m^(6)A modification,and its mutations lead to intellectual disability,microcephaly,and facial dysmorphism in patients.However,the role of METTL5 in craniofacial development remains poorly understood.This study demonstrates that Mettl5 knockout mice exhibit poor ossification,widened cranial sutures,and a cleidocranial dysplasia-like phenotype.Deletion of Mettl5 leads to increased proliferation and decreased osteogenic differentiation of suture mesenchymal stem cells.Mechanistically,we find that Wnt signaling is significantly downregulated after Mettl5 knockout.Overall,we reveal an essential role of METTL5 in craniofacial development and osteogenic differentiation of suture mesenchymal stem cells,making METTL5 a potential diagnostic and therapeutic target for craniofacial developmental diseases. | Kexin Lei Ruoshi Xu Qian Wang Qiuchan Xiong Xinyi Zhou Qiwen Li Dutmanee Seriwatanachai Shuibin Lin Chenchen Zhou Quan Yuan | 2023 | Fundamental Research2023，3，3： | 0 |
| 9 | N6-methyladenosine(m6A)modification of ribosomal RNAs(rRNAs):Critical roles in mRNA translation and diseases显示文摘key components of the ribosome and the most abundant RNA species,the rRNAs are modified during ribosome formation.N^(6)-methyladenosine(m^(6)A)is a conserved RNA modification occurring on different RNA species including rRNAs.Recently,it has been reported that ZCCHC4 and METTL5 are methyltransferases that mediate m^(6)A modification of human 28S and 18S rRNA,respectively.The newly discovered biological functions of the two methyltransferases include regulation of mRNA translation,cell proliferation,cell differentiation,stress response,and other biological processes.Both of them,especially METTL5,have been proved to be associated with a variety of diseases such as intellectual disability,cancer,congenital dysplasia and have potential clinical application as biomarkers and therapeutic targets. | Kexin Lei Shuibin Lin Quan Yuan | 2023 | Genes & Diseases2023，10，1： | 0 |
| 10 | mRNA alternative polyadenylation (APA) in regulation of gene expression and diseases显示文摘The mRNA polyadenylation plays essential function in regulation of mRNA metabolism.Mis-regulations of mRNA polyadenylation are frequently linked with aberrant gene expression and disease progression.Under the action of polyadenylate polymerase,poly(A)tail is synthesized after the polyadenylation signal(PAS)sites on the mRNAs.Alternative polyadenylation(APA)often occurs in mRNAs with multiple poly(A)sites,producing different 3'ends for transcript variants,and therefore plays important functions in gene expression regulation.In this review,we first summarize the classical process of mRNA 3'-terminal formation and discuss the length control mechanisms of poly(A)innucleus and cytoplasm.Thenwe review the research progress on alternative polyadenylation regulation and the APA site selection mechanism.Finally,we summarize the functional roles of APA in the regulation of gene expression and diseases including cancers. | Siyao Guo Shuibin Lin | 2023 | Genes & Diseases2023，10，1： | 0 |
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