bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022‒01‒02
fourteen papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics
  1. Modulation of Phase Separation by RNA: A Glimpse on N6-Methyladenosine Modification.
  2. N6-Methyladenosine RNA Modification in the Tumor Immune Microenvironment: Novel Implications for Immunotherapy.
  3. N6-methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal cancer.
  4. Effect of m6A methyltransferase METTL3 -mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer.
  5. N6-methyladenosine(m6A) demethylase FTO regulates cellular apoptosis following cobalt-induced oxidative stress.
  6. METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation.
  7. Ribosome 18S m6A methyltransferase METTL5 promotes pancreatic cancer progression by modulating c‑Myc translation.
  8. Integrative 5-Methylcytosine Modification Immunologically Reprograms Tumor Microenvironment Characterizations and Phenotypes of Clear Cell Renal Cell Carcinoma.
  9. The RNA Methylation Modification 5-Methylcytosine Impacts Immunity Characteristics, Prognosis and Progression of Oral Squamous Cell Carcinoma by Bioinformatics Analysis.
  10. Specific Regulation of m6A by SRSF7 Promotes the Progression of Glioblastoma.
  11. Targeted Methylation of the LncRNA NEAT1 Suppresses Malignancy of Renal Cell Carcinoma.
  12. m6A Modification-Mediated DUXAP8 Regulation of Malignant Phenotype and Chemotherapy Resistance of Hepatocellular Carcinoma Through miR-584-5p/MAPK1/ERK Pathway Axis.
  13. FGL1 as a Novel Mediator and Biomarker of Malignant Progression in Clear Cell Renal Cell Carcinoma.
  14. Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2.
  1. Front Cell Dev Biol. 2021 ;9 786454
    Modulation of Phase Separation by RNA: A Glimpse on N6-Methyladenosine Modification.
    Yingfeng Su, Yasen Maimaitiyiming, Lingfang Wang, Xiaodong Cheng, Chih-Hung Hsu.
      Phase separation is the driving force behind formation of various biomolecular condensates (BioMCs), which sub-compartmentalize certain cellular components in a membraneless manner to orchestrate numerous biological processes. Many BioMCs are composed of proteins and RNAs. While the features and functions of proteins are well studied, less attention was paid to the other essential component RNAs. Here, we describe how RNA contributes to the biogenesis, dissolution, and properties of BioMCs as a multivalence providing scaffold for proteins/RNA to undergo phase separation. Specifically, we focus on N6-methyladenosine (m6A), the most widely distributed dynamic post-transcriptional modification, which would change the charge, conformation, and RNA-binding protein (RBP) anchoring of modified RNA. m6A RNA-modulated phase separation is a new perspective to illustrate m6A-mediated various biological processes. We summarize m6A main functions as "beacon" to recruit reader proteins and "structural switcher" to alter RNA-protein and RNA-RNA interactions to modulate phase separation and regulate the related biological processes.
    Keywords:  N6-methyladenosine (m 6 A); RNA modification; RNA–RNA interaction; RNA–protein interaction; biomolecular condensate; multivalence; phase separation
    DOI:  https://doi.org/10.3389/fcell.2021.786454
  2. Front Immunol. 2021 ;12 773570
    N6-Methyladenosine RNA Modification in the Tumor Immune Microenvironment: Novel Implications for Immunotherapy.
    Liting Guo, Hui Yang, Chenfei Zhou, Yan Shi, Lei Huang, Jun Zhang.
      N6-methyladenosine (m6A) methylation is one of the most common modifications of RNA in eukaryotic cells, and is mainly regulated by m6A methyltransferases (writers), m6A demethylases (erasers), and m6A binding proteins (readers). Recently, accumulating evidence has shown that m6A methylation plays crucial roles in the regulation of the tumor immune microenvironment, greatly impacting the initiation, progression, and metastasis processes of various cancers. In this review we first briefly summarizes the m6A-related concepts and detection methods, and then describes in detail the associations of m6A methylation modification with various tumor immune components especially immune cells (e.g., regulatory T cells, dendritic cells, macrophages, and myeloid-derived suppressor cells) in a variety of cancers. We discuss the relationship between m6A methylation and cancer occurrence and development with the involvement of tumor immunity highlighted, suggesting novel markers and potential targets for molecular pathological diagnosis and immunotherapy of various cancers.
    Keywords:  N6-methyladenosine methylation; immunotherapy; m6A; tumor immune microenvironment; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2021.773570
  3. Gastroenterology. 2021 Dec 27. pii: S0016-5085(21)04165-2. [Epub ahead of print]
    N6-methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal cancer.
    Shiyan Wang, Shanshan Gao, Yong Zeng, Lin Zhu, Yulin Mo, Chi Chun Wong, Yi Bao, Peiran Su, Jianning Zhai, Lina Wang, Fraser Soares, Xin Xu, Huarong Chen, Kebria Hezaveh, Xinpei Ci, Aobo He, Tracy McGaha, Catherine O'Brien, Robert Rottapel, Wei Kang, Jianfeng Wu, Gang Zheng, Zongwei Cai, Jun Yu, Housheng Hansen He.
      BACKGROUND & AIMS: N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated.METHODS: Ythdf1 knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-ARHGEF2 was evaluated using siRNA encapsulated by lipid nanoparticles (LNP).
    RESULTS: DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids, and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 mRNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo.
    CONCLUSIONS: We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.
    Keywords:  ARHGEF2; N6-methyladenosine; YTHDF1; colorectal cancer; nanoparticle
    DOI:  https://doi.org/10.1053/j.gastro.2021.12.269
  4. J Biochem Mol Toxicol. 2021 Dec 28. e22922
    Effect of m6A methyltransferase METTL3 -mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer.
    Sumei Li, Fengru Jiang, Feiyu Chen, Yingzhao Deng, Xiaoping Pan.
      N6-methyladenosine (m6A) methyltransferase METTL3 has been implicated in carcinogenesis, which may be associated the overexpression of MALAT1. However, the downstream mechanics actions remain largely unknown. This study intends to probe the downstream mechanism of the N6-methyladenosine (m6 A) methyltransferase METTL3 and MALAT1 in adriamycin resistance in breast cancer. Through Bioinformatics databases lncMAP, TCGA and GTEx, we predicted the downstream transcription factors E2F1 and AGR2 of MALAT1 in breast cancer. The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases were used to screen the downstream target genes of MALAT1. MeRIP-qPCR was used to detect the m6 A level of MALAT1 in cells. RIP was used to detect the binding between MALAT1 and E2F1, and chromatin immunoprecipitation (ChIP) for the binding of E2F1 to AGR2 promoter. Cell Counting Kit-8 and colony formation assays were used to detect cell viability. Transwell was used to detect cell invasion. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were used to detect the expression of related genes and proteins. A nude mouse xenograft tumor model was established to observe the effect of METTL3 on adriamycin resistance of breast cancer. The total survival of mice after exogenous gene silencing was analyzed by the Kaplan-Meier method. METTL3 was highly expressed in adriamycin-resistant breast cancer cells. METTL3 promotes adriamycin resistance in breast cancer cells. METTL3 mediates the expression of MALAT1 in adriamycin-resistant breast cancer through m6 A. MALAT1 increases adriamycin resistance in breast cancer cells by recruiting E2F1 to activate AGR2 transcription. METTL3 can regulate the expression of MALAT1 through m6 A, mediate the E2F1/AGR2 axis, and promote the adriamycin resistance of breast cancer. METTL3 may modify MALAT1 protein through m6 A, recruit E2F1 and activate downstream AGR2 expression, thus promoting adriamycin resistance in breast cancer.
    Keywords:  E2F1; MALAT1; adriamycin resistance; anterior gradient 2; breast cancer; m6A; methyltransferase; methyltransferase-like 3
    DOI:  https://doi.org/10.1002/jbt.22922
  5. Environ Pollut. 2021 Dec 27. pii: S0269-7491(21)02331-9. [Epub ahead of print] 118749
    N6-methyladenosine(m6A) demethylase FTO regulates cellular apoptosis following cobalt-induced oxidative stress.
    Jianping Tang, Qianqian Su, Zhenkun Guo, Jinfu Zhou, Fuli Zheng, Guangxia Yu, Wenya Shao, Hong Hu, Siying Wu, Huangyuan Li.
      Cobalt is an environmental toxicant that is known to damage human health. However, the molecular mechanisms underlying cobalt-induced neurotoxicity have not been elucidated in detail. In the present research, we used human neuroglioma H4 cells as an in vitro model. Cells were exposed to CoCl2 (0, 100, 200, 400 μM) for 24 h. We performed m6A sequencing techniques and constructed FTO-knockdown/FTO-overexpressing cells to investigate the role of FTO-mediated m6A modification in regulating apoptosis following CoCl2 induced oxidative stress. Our study has shown CoCl2 exposure led to the decrease of demethylase FTO as well as elevated oxidative stress. However, NAC treatment could partly reverse the reduction of FTO expression as well as the degree of ROS via eliminating oxidative stress. Meanwhile, MeRIP-seq and RNA-seq further revealed the potential function m6A modification in regulating apoptosis. More importantly, KEGG pathway and Gene ontology (GO) analyses further elucidated that the differentially m6A-modified genes were aggregated in apoptosis-related pathways. Mechanistic analysis indicated that knockdown of FTO facilitated CoCl2-induced apoptosis via caspase activation and G1/S cell cycle arrest. Nevertheless, overexpression of FTO partly attenuated the increased apoptosis following CoCl2 exposure. More notably, we observed that FTO regulated apoptosis in an m6A-dependent manner. Therefore, our findings reveal that CoCl2 induced ROS affected the m6A modification of apoptosis-related genes by decreasing the expression of FTO, thereby resulting in the activation of apoptosis. These findings provide important insights into CoCl2-induced apoptosis and m6A modification and propose a novel strategy for studying environmental toxicant-related neurodegeneration.
    Keywords:  Apoptosis; Cobalt chloride; Epigenetic regulation; Oxidative stress; m(6)A modification
    DOI:  https://doi.org/10.1016/j.envpol.2021.118749
  6. Biochim Biophys Acta Gene Regul Mech. 2021 Dec 27. pii: S1874-9399(21)00100-0. [Epub ahead of print] 194782
    METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation.
    Da Cheng, Cichun Wu, Ying Li, Yao Liu, Juan Mo, Lei Fu, Shifang Peng.
      Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF) is a clinical syndrome of severe liver damage. HBV infection is affected by N6-methyladenosine (m6A) RNA modification. Here, we investigated whether methyltransferase-like 3 (METTL3)-mediated m6A methylation can affect ACLF. Human hepatic cells (THLE-2) were treated with lipopolysaccharide (LPS) to induce cell damage. Proliferation, apoptosis and m6A modification were measured by MTT assay, flow cytometry and Dot blot assay. Our results showed that HBV infection significantly enhanced the levels of m6A modification and elevated the expression of METTL3 and mature-miR-146a-5p in THLE-2 cells, which was repressed by cycloleucine (m6A inhibitor). METTL3 overexpression enhanced m6A modification and promoted mature-miR-146a-5p expression. METTL3 overexpression promoted HBV replication and apoptosis, enhanced the levels of pro-inflammatory cytokines, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and repressed cell proliferation in THLE-2 cells, which attributed to repress miR-146a-5p maturation. Moreover, a severe liver failure mouse model was established by HBV infection to verify the impact of METTL3 knockdown on liver damage in vivo. HBV-infection led to a severe liver damage and increase of apoptosis in hepatic tissues of mice, which was abolished by METTL3 knockdown. METTL3 knockdown reduced METTL3 expression and impeded miR-146a-5p maturation in HBV-infected mice. In conclusion, this work demonstrates that METTL3 inhibition ameliorates liver damage in mouse with HBV-associated ACLF, which contributes to repress miR-146a-5p maturation. Thus, this article suggests a novel therapeutic avenue to prevent and treat HBV-associated ACLF.
    Keywords:  Acute-on-chronic liver failure; Hepatitis B virus; Liver cell damage; METTL3; m(6)A methylation; miR-146a-5p
    DOI:  https://doi.org/10.1016/j.bbagrm.2021.194782
  7. Int J Oncol. 2022 Jan;pii: 9. [Epub ahead of print]60(1):
    Ribosome 18S m6A methyltransferase METTL5 promotes pancreatic cancer progression by modulating c‑Myc translation.
    Hua Huang, Huan Li, Ruining Pan, Sijia Wang, Aamir Ali Khan, Yue Zhao, Huiyu Zhu, Xinhui Liu.
      Methyltransferase N6‑adenosine (METTL5) is a methyltransferase that specifically catalyzes 18S rRNA N6 methylation at adenosine 1832 (m6A1832), which is located in a critical position in the decoding center, therefore suggesting its potential importance in the regulation of translation. However, the underlying mechanism of METTL5‑mediated translation regulation of specific genes and its biological functions are largely undefined. To the best of our knowledge, the present study demonstrated for the first time that METTL5 was an oncogene that promoted cell proliferation, migration, invasion and tumorigenesis in pancreatic cancer. In addition, the oncogenic function of METTL5 may involve an increase in c‑Myc translation, as evidenced by the fact that the oncogenic effect caused by METTL5 overexpression could be abolished by c‑Myc knockdown. Notably, m6A modifications at the 5' untranslated region (5'UTR) and coding DNA sequence region (near the 5'UTR) of c‑Myc mRNA played a critical role in the specific translation regulation by METTL5. In addition, it was further demonstrated that METTL5 and its cofactor tRNA methyltransferase activator subunit 11‑2 synergistically promote pancreatic cancer progression. These findings revealed important roles for METTL5 in the development of pancreatic cancer and present the METTL5/c‑Myc axis as a novel therapeutic strategy for treatment.
    Keywords:  N6 methyladenosine; c‑Myc; methyltransferase N6‑adenosine; pancreatic cancer; tRNA methyltransferase activator subunit 11‑2
    DOI:  https://doi.org/10.3892/ijo.2021.5299
  8. Front Cell Dev Biol. 2021 ;9 772436
    Integrative 5-Methylcytosine Modification Immunologically Reprograms Tumor Microenvironment Characterizations and Phenotypes of Clear Cell Renal Cell Carcinoma.
    Wenhao Xu, Wenkai Zhu, Xi Tian, Wangrui Liu, Yuanyuan Wu, Aihetaimujiang Anwaier, Jiaqi Su, Shiyin Wei, Yuanyuan Qu, Hailiang Zhang, Dingwei Ye.
      The tumor microenvironment (TME) affects the biologic malignancy of clear cell renal cell carcinoma (ccRCC). The influence of the 5-methylcytosine (m5C) epigenetic modification on the TME is unknown. We comprehensively assessed m5C modification patterns of 860 ccRCC samples (training, testing, and real-world validation cohorts) based on 17 m5C regulators and systematically integrated the modification patterns with TME cell-infiltrating characterizations. Our results identified distinct m5C modification clusters with gradual levels of immune cell infiltration. The distinct m5C modification patterns differ in clinicopathological features, genetic heterogeneity, patient prognosis, and treatment responses of ccRCC. An elevated m5C score, characterized by malignant biologic processes of tumor cells and suppression of immunity response, implies an immune-desert TME phenotype and is associated with dismal prognosis of ccRCC. Activation of exhausted T cells and effective immune infiltration were observed in the low m5C score cluster, reflecting a noninflamed and immune-excluded TME phenotype with favorable survival and better responses to immunotherapy. Together, these findings provide insights into the regulation mechanisms of DNA m5C methylation modification patterns on the tumor immune microenvironment. Comprehensive assessment of tumor m5C modification patterns may enhance our understanding of TME cell-infiltrating characterizations and help establish precision immunotherapy strategies for individual ccRCC patients.
    Keywords:  5-methylcytosine; clear cell renal cell carcinoma; immune checkpoint therapies; machine learning algorithm; prognosis; renal cell carcinoma (RCC) clear cell renal cell carcinoma (CCRCC); tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2021.772436
  9. Front Bioeng Biotechnol. 2021 ;9 760724
    The RNA Methylation Modification 5-Methylcytosine Impacts Immunity Characteristics, Prognosis and Progression of Oral Squamous Cell Carcinoma by Bioinformatics Analysis.
    Li Gao, Ru Chen, Masahiro Sugimoto, Masanobu Mizuta, Lei Zhou, Yo Kishimoto, Xinsheng Huang, Koichi Omori.
      Disorders pertaining to 5-methylcytosine (m5C) modifications are involved in the pathological process of many diseases. However, the effect of m5C on the tumorigenesis and progression of oral squamous cell carcinoma (OSCC) remains unclear. In this study, we integrated the genomic and clinical data of 558 OSCC samples to comprehensively evaluate m5C modification patterns. Based on 16 m5C methylation regulators, two m5C modification clusters were identified with distinct tumor immune microenvironment (TIME) characteristics and prognosis in OSCC. We then performed weighted gene co-expression network analysis (WGCNA) to identify m5C modification cluster-related modules. Genes in the selected module were chosen to construct the m5Cscore scoring system for evaluating m5C modification pattern in individual OSCC patients. Patients with a high m5Cscore had higher immune, stromal, and ESTIMATE scores; lower tumor purity score; lower immune activity; and higher tumor mutational burden. The overall survival rate and progression-free survival rate were markedly worse and the tumor recurrence rate was higher in OSCC patients with a high m5Cscore. Furthermore, patients with oral leukoplakia who also had a high m5Cscore had a higher risk of deterioration to OSCC. This study demonstrated that m5C modification patterns might affect the TIME in OSCC. m5Cscore may provide a new approach for predicting the prognosis and progression of OSCC.
    Keywords:  5-methylcytosine (m5C); RNA methylation modification; oral squamous cell carcinoma; prognosis; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fbioe.2021.760724
  10. Genomics Proteomics Bioinformatics. 2021 Dec 22. pii: S1672-0229(21)00252-7. [Epub ahead of print]
    Specific Regulation of m6A by SRSF7 Promotes the Progression of Glioblastoma.
    Yixian Cun, Sanqi An, Haiqing Zheng, Jing Lan, Wenfang Chen, Wanjun Luo, Chengguo Yao, Xincheng Li, Xiang Huang, Xiang Sun, Zehong Wu, Yameng Hu, Ziwen Li, Shuxia Zhang, Geyan Wu, Meisongzhu Yang, Miaoling Tang, Ruyuan Yu, Xinyi Liao, Guicheng Gao, Wei Zhao, Jinkai Wang, Jun Li.
      Serine/arginine-rich splicing factor 7 (SRSF7), a known splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N6-methyladenosine (m6A) co-methylation network analysis across diverse cell lines, we find that the gene expression of SRSF7 is positively correlated with glioblastoma cell-specific m6A methylation. We then indicate that SRSF7 is a novel m6A regulator, which specifically facilitates the m6A methylation near its binding sites on the mRNAs involved in cell proliferation and migration, through recruiting methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of glioblastoma cells largely dependent on the presence of the m6A methyltransferase. The two m6A sites on PDZ binding kinase (PBK) are regulated by SRSF7 and partially mediate the effects of SRSF7 in glioblastoma cells through recognition by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Together, our discovery reveals a novel role of SRSF7 in regulating m6A and validates the presence and functional importance of temporal- and spatial-specific regulation of m6A mediated by RNA binding proteins (RBPs).
    Keywords:  Cell-specific regulation; Glioblastoma; PDZ binding kinase; Serine/arginine-rich splicing factor 7; m(6)A
    DOI:  https://doi.org/10.1016/j.gpb.2021.11.001
  11. Front Cell Dev Biol. 2021 ;9 777349
    Targeted Methylation of the LncRNA NEAT1 Suppresses Malignancy of Renal Cell Carcinoma.
    Jieqing Chen, Xinhui Liao, Jianli Cheng, Ganglin Su, Fen Yuan, Zhongfu Zhang, Jianting Wu, Hongbing Mei, Wanlong Tan.
      Long-chain non-coding RNA (LncRNA) has been found to play an important role in the regulation of the occurrence and progression of renal cell carcinoma (RCC). In this study, we demonstrated that LncRNA NEAT1 expression and m6A methylation level was decreased in RCC tissues. Further, the downregulated expression level of LncRNA NEAT1 was associated with poor prognosis for RCC patients. Then we used CRIPSR/dCas13b-METTL3 to methylate LncRNA NEAT1 in RCC cells. The results showed that the expression level of LncRNA NEAT1 was upregulated after methylated by dCas13b-METTL3 in RCC cells. And the proliferation and migration ability of RCC cells was decreased after methylated LncRNA NEAT1. Finally, we examined the effect of LncRNA NEAT1 hypermethylation on the transcriptome. We found differentially expressed genes in RCC cells were associated with "cGMP-PKG signaling pathway", "Cell adhesion molecules" and "Pathways in cancer". In conclusion, CRISPR/Cas13b-METTL3 targeting LncRNA NEAT1 m6A methylation activates LncRNA NEAT1 expression and provides a new target for treatment of RCC.
    Keywords:  NEAT1; RCC = renal cell cancer; dCas13b; lncRNA; m6A (N6-methyladenosine)
    DOI:  https://doi.org/10.3389/fcell.2021.777349
  12. Front Cell Dev Biol. 2021 ;9 783385
    m6A Modification-Mediated DUXAP8 Regulation of Malignant Phenotype and Chemotherapy Resistance of Hepatocellular Carcinoma Through miR-584-5p/MAPK1/ERK Pathway Axis.
    Zefeng Liu, Jin Lu, He Fang, Jiyao Sheng, Mengying Cui, Yongsheng Yang, Bo Tang, Xuewen Zhang.
      Hepatocellular carcinoma (HCC) has a poor prognosis due to its high malignancy, rapid disease progression, and the presence of chemotherapy resistance. Long-stranded non-coding RNAs (lncRNAs) affect many malignant tumors, including HCC. However, their mechanism of action in HCC remains unclear. This study aimed to clarify the role of DUXAP8 in regulating the malignant phenotype and chemotherapy resistance in HCC. Using an in vivo xenograft tumor model, the regulatory functions and mechanisms of lncRNA DUXAP8 in the progression and response of HCC to chemotherapy were explored. It was found that DUXAP8 was significantly upregulated in a patient-derived xenograft tumor model based on sorafenib treatment, which is usually associated with a relatively poor prognosis in patients. In HCC, DUXAP8 maintained its upregulation in the expression by increasing the stability of m6A methylation-mediated RNA. DUXAP8 levels were positively correlated with the proliferation, migration, invasion, and chemotherapy resistance of HCC in vivo and in vitro. In the mechanistic study, it was found that DUXAP8 competitively binds to miR-584-5p through a competing endogenous RNA (ceRNA) mechanism, thus acting as a molecular sponge for miR-584-5p to regulate MAPK1 expression, which in turn activates the MAPK/ERK pathway. These findings can provide ideas for finding new prognostic indicators and therapeutic targets for patients with HCC.
    Keywords:  DUXAP8; MAPK1; chemotherapy resistance; hepatocellular carcinoma; m6A methylation modification; malignant phenotype; miR-584-5p
    DOI:  https://doi.org/10.3389/fcell.2021.783385
  13. Front Oncol. 2021 ;11 756843
    FGL1 as a Novel Mediator and Biomarker of Malignant Progression in Clear Cell Renal Cell Carcinoma.
    Zheng Lv, Bo Cui, Xing Huang, Hua-Yi Feng, Tao Wang, Han-Feng Wang, Yun-Dong Xuan, Hong-Zhao Li, Xin Ma, Yan Huang, Xu Zhang.
      Clear cell renal cell carcinoma (ccRCC), which is the most prevalent renal cell carcinoma subtype, has a poor prognosis. Emerging strategies for enhancing the immune response in ccRCC therapy are currently being investigated. Fibrinogen-like Protein 1(FGL1) is a novel mechanism that tumors may use to evade the immune system by binding LAG-3 and negatively regulating T cells. In this study, we aimed at investigating the underlying mechanism of FGL1 in ccRCC, and its expression and prognostic value. We found that FGL1 was upregulated in tumor tissues and plasma specimens of ccRCC patients. High FGL1 expression predicted a poor prognosis for ccRCC patients. We also discovered that overexpression of FGL1 enhances RCC cell migration, invasion, and metastasis by activating the epithelial-to-mesenchymal transition (EMT). Consistent with these results, we identified a significant positive correlation between expression of FGL1 and EMT-related genes through tissue microarray analysis. Gene-expression analysis revealed that FGL1-deficient ccRCC cell lines had altered transcriptional output in inflammatory response, cell-cell signaling, negative regulation of T cell activation, and intracellular signal transduction. Depletion of FGL1 significantly inhibited tumor growth and lung metastasis in orthotopic xenograft mouse model. Infiltration of myeloid-derived CD11b+ and Ly6G+ immune cells in tumor microenvironment (TME) was strikingly decreased when FGL1 expression reduced. Therefore, increased FGL1 expression in ccRCC is positively correlated with poor prognosis. Mechanistically, FGL1 facilitates the EMT process and modulates TME, which promotes ccRCC progression and metastasis. Consequently, targeting FGL1 can potentially improve clinical outcome of ccRCC patients.
    Keywords:  biomarker; clear cell renal cell carcinoma; epithelial to mesenchymal transition; fibrinogen-like protein 1; progression
    DOI:  https://doi.org/10.3389/fonc.2021.756843
  14. Cell Discov. 2021 Dec 28. 7(1): 122
    Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2.
    Kyle Delaney, Minjia Tan, Zhesi Zhu, Jinjun Gao, Lunzhi Dai, Sunjoo Kim, Jun Ding, Maomao He, Levon Halabelian, Lu Yang, Prabakaran Nagarajan, Mark Robert Parthun, Sangkyu Lee, Saadi Khochbin, Yujun George Zheng, Yingming Zhao.
      Histone lysine crotonylation is a posttranslational modification with demonstrated functions in transcriptional regulation. Here we report the discovery of a new type of histone posttranslational modification, lysine methacrylation (Kmea), corresponding to a structural isomer of crotonyllysine. We validate the identity of this modification using diverse chemical approaches and further confirm the occurrence of this type of histone mark by pan specific and site-specific anti-methacryllysine antibodies. In total, we identify 27 Kmea modified histone sites in HeLa cells using affinity enrichment with a pan Kmea antibody and mass spectrometry. Subsequent biochemical studies show that histone Kmea is a dynamic mark, which is controlled by HAT1 as a methacryltransferase and SIRT2 as a de-methacrylase. Altogether, these investigations uncover a new type of enzyme-catalyzed histone modification and suggest that methacrylyl-CoA generating metabolism is part of a growing number of epigenome-associated metabolic pathways.
    DOI:  https://doi.org/10.1038/s41421-021-00344-4
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