The roles of N6-methyladenosine methylation in the regulation of bone development, bone remodeling and osteoporosis.

ABSTRACT Emerging evidence has emphasized the critical roles played by N6-methyladenosine RNA (m6A) modification in colorectal carcinoma (CRC) initiation and progression. However, the roles and mechanism of m6A and KIAA1429 in CRC progression require further clarification. Here, our research aimed to investigate the functions of KIAA1429 in CRC tumorigenesis. Results indicated that KIAA1429 up-regulation closely correlated to the poor prognosis of CRC patients. Bio-functional assays demonstrated that KIAA1429 promoted the aerobic glycolysis, including glucose uptake, lactate production, ATP generation and extracellular acidification rate (ECAR). Mechanistically, KIAA1429 positively up-regulated HK2 level via increasing its mRNA stability by binding the m6A site of HK2 mRNA via m6A-independent manner. Collectively, our work indicates that KIAA1429 has the potential to promote CRC carcinogenesis by targeting HK2 via m6A-independent manner, providing insight into the critical roles of m6A in CRC. Graphical abstract

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2022.2065952?needAccess=true

N6-methyladenosine methyltransferase KIAA1429 elevates colorectal cancer aerobic glycolysis via HK2-dependent manner

Abstract Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast. 

/pdf/the-role-mechanism-and-application-of-rna-methyltransferase-2bqqe36w.pdf

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

https://molecular-cancer.biomedcentral.com/counter/pdf/10.1186/s12943-022-01634-5

N6 -Methyladenosine (m6 A) is an important RNA modification catalyzed by methyltransferase-like 3 (METTL3) and METTL14. m6 A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m6 A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m6 A levels. The amino acid regions 450-454 and 464-480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m6 A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m6 A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer. 

<scp>METTL3</scp>
            protects
            <scp>METTL14</scp>
            from
            <scp>STUB1</scp>
            ‐mediated degradation to maintain
            <scp>
              m
              <sup>6</sup>
              A
            </scp>
            homeostasis

RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N6-methyladenine (m6A) is the most abundant RNA modification. Methyltransferase-like 14 (METTL14) is the central component of the m6A methylated transferase complex, which is involved in the dynamic reversible process of m6A modification. METTL14 acts as both an oncogene and tumor suppressor gene to regulate the occurrence and development of various cancers. The abnormal m6A level induced by METTL14 is related to tumorigenesis, proliferation, metastasis, and invasion. To date, the molecular mechanism of METTL14 in various malignant tumors has not been fully studied. In this paper, we systematically summarize the latest research progress on METTL14 as a new biomarker for cancer diagnosis and its biological function in human tumors and discuss its potential clinical application. This study aims to provide new ideas for targeted therapy and improved prognoses in cancer. 

/pdf/functions-mechanisms-and-therapeutic-implications-of-mettl14-k717c327.pdf

Functions, mechanisms, and therapeutic implications of METTL14 in human cancer

Objective: To explore the feasibility of sampling Chinese patients by suction curettage for cytological and histological screening of endometrial cancer related to Lynch syndrome. Methods: This retrospective study enrolled patients who underwent endometrial biopsy at our hospital between May 2018 and January 2019. Endometrial sampling (cytological and micro-histological specimens) was conducted by suction curettage. The gold standard for diagnosis was traditional sharp dilation and curettage (D&C). The sensitivity, specificity, and diagnostic accuracy of cytology, micro-histology, and the combination of cytology and micro-histology were calculated. Additionally, receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic efficiency of three screening methods. Mismatch repair proteins were further detected using immunohistochemistry (IHC) in endometrial cancer. Results: This retrospective finally enrolled 100 patients, which satisfactory samples were obtained from 96 patients for liquid-based cytology and 93 patients for microtissue histology. The concordance rates with D&C, sensitivity, and specificity were 94.8%, 76.9%, and 97.5% for liquid-based cytology, 96.8%, 84.6%, and 98.8% for microtissue histology, and 99.0%, 92.3%, and 100.0% for liquid-based cytology and microtissue histology combined, respectively. The AUC of ROC curves in liquid-based cytology, microtissue histology, and the combined methods for diagnostic ability were 0.873, 0.917, and 0.962, respectively. Absence rates of MLHl, MSH2, MSH6, and PMS2 proteins were 15.3% (2/13), 0% (0/13), 7.7% (1/13), and 15.3% (2/13) in the 13 endometrial cancer samples. Conclusion: Liquid-based cytology and microtissue histology samples from suction curettage combined IHC are useful for endometrial cancer screening.

Screening of Endometrial Cancer Related to Lynch Syndrome in China by Suction Curettage-Based Cytology and Histology: A Retrospective Study

The recurrence and metastasis of children with mediastinal neuroblastoma (NB) are also occurred after surgery, chemotherapy, or radiotherapy. Strategies targeting the tumor microenvironment have been reported to improve survival; however, thorough investigations of monocytes and tumor-associated macrophages (Mϕs) with specialized functions in NB are still lacking. Our data first demonstrated polypyrimidine tract binding protein 2 (PTBP2) as a possible identifier in patients with mediastinal NB screened by proteomic profiling and that PTBP2 predicted good outcomes. Functional studies revealed that PTBP2 in NB cells induced the chemotactic activity and repolarization of tumor-associated monocytes and Mϕs, which, in turn, inhibited NB growth and dissemination. Mechanistically, PTBP2 prevents interferon regulatory factor 9 alternative splicing and upregulates signal transducers and activators of transcription 1 to stimulate C-C motif chemokine ligand 5 (CCL5) and interferon-stimulated gene factor-dependent type I interferon secretion, to induce monocyte/Mϕs chemotaxis, and to sustain monocytes in a proinflammatory phenotype. Our study defined a critical event of PTBP2-induced monocytes/Mϕs in NB progression and revealed that RNA splicing occurred by PTBP2 benefits immune compartmentalization between NB cells and monocytes. This work revealed the pathological and biological role of PTBP2 in NB development and indicates that PTBP2-induced RNA splicing benefits immune compartmentalization and predicted a favorable prognosis in mediastinal NB.

https://spj.science.org/doi/pdf/10.34133/research.0033?download=true

PTBP2-Mediated Alternative Splicing of IRF9 Controls Tumor-Associated Monocyte/Macrophage Chemotaxis and Repolarization in Neuroblastoma Progression

Background TMEM59L is a newly discovered transmembrane protein; its functions in cancer remain unknown. This study was designed to reveal the prognostic value and the functional role of TMEM59L in cancer. Methods The gene expression profiles, methylation data, and corresponding clinical data of TMEM59L were retrieved from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression database. Survival analysis was employed to calculate the pan-cancer prognostic value of TMEM59L. The correlation between TMEM59L expression and tumor immune microenvironment, as well as DNA methylation dynamics and genomic heterogeneity across cancers were assessed based on data from TCGA. Results Our findings revealed that distinct differences of TMEM59L mRNA expression were observed in different cancer types and that higher TMEM59L expression was observed in the advanced pathological stage and associated with worse prognosis in kidney renal papillary cell carcinoma, bladder urothelial carcinoma, colon adenocarcinoma, and kidney renal clear cell carcinoma. Pathway analysis indicated that TMEM59L exerted a key influence in cancer development and in immune- and cancer-associated pathways such as epithelial–mesenchymal transition and TGF-β signaling. Moreover, correlation analysis hinted at a negative correlation of TMEM59L expression with CD8 T cells, activated CD4 T cells, and several immunomodulators, including IDO1, TIGIT, PD-L1, CTLA-4, and BTLA in various cancers. Survival analysis indicated that the hypermethylation of TMEM59L gene was associated with longer survival times. A significant correlation was also observed between TMEM59L expression and immunophenoscore, homologous recombination deficiency, loss of heterozygosity, tumor stemness score, and neoantigens in various cancers. Importantly, we also identified numerous potential agents that may target TMEM59L. Conclusion Our study revealed the prognostic value as well as the genomic and immunological characteristics of TMEM59L in cancers, highlighting the promising potential for TMEM59L as a prognostic cancer biomarker and a therapeutic target.

https://www.frontiersin.org/articles/10.3389/fimmu.2022.1054157/pdf

Huiqin Guo

Papers

Functions, mechanisms, and therapeutic implications of METTL14 in human cancer

Screening of Endometrial Cancer Related to Lynch Syndrome in China by Suction Curettage-Based Cytology and Histology: A Retrospective Study

PTBP2-Mediated Alternative Splicing of IRF9 Controls Tumor-Associated Monocyte/Macrophage Chemotaxis and Repolarization in Neuroblastoma Progression

Prognostic value of TMEM59L and its genomic and immunological characteristics in cancer