ALKBH5 regulates STAT3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6A-YTHDF2-dependent manner

Yang, Zechuan; Cai, Zhuo; Yang, Chun; Luo, Zhengqiang; Bao, Xiaoyong

doi:10.1016/j.ebiom.2022.104019

Cited by 45 publications

(28 citation statements)

References 50 publications

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“…In addition, knock out of SOCS3 in mice can restrain cell proliferation and growth. In a mouse model, METTL3 was reported to modify SOCS3 mRNAs by m6A methylation, which decreased the degradation of SOCS3 and increased its translation, thereby suppressing JAK2/STAT3 signaling and consequently promote cell proliferation and growth 39 . Moreover, we found that m6A modi cation are involved in regulating SOCS3 translation in a METTL3/ IGF2BP1orchestrated manner.…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

Zhu

Lian

Chen

et al. 2022

Preprint

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N6-methyladenosine (m6A)-associated mechanisms are involved in cellular metabolic activities; however, their role in skeletal muscle stem cell (SkMSC) senescence is unknown. In this study, m6A RNA modification and METTL3 expression were decreased in aged SkMSCs from mice. Transcriptional analysis of m6A modification further revealed that suppressor of cytokine signaling 3 (SOCS3) was downregulated in aged SkMSCs, and that downregulation of METTL3 promoted SkMSC senescence. In addition, the upregulation of METTL3 alleviated the senescence of SkMSCs. Mechanistically, deletion of m6A modifications promoted senescence and inhibited SOCS3 expression, whereas downregulation of SOCS3 promoted senescence. Moreover, insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) was identified as an important regulator in the recognition and stabilization of m6A modified SOCS3 expression. IGF2BP1 binds to SOCS3 and reinforces its stability by suppressing the phosphorylation of JAK2/STAT3. Therefore, METTL3 inhibits SkMSC senescence through m6A modification-dependent stabilization of SOCS3 expression and inhibition of JAK2-STAT3 signaling. This study thus highlights a novel mechanism underlying SkMSC senescence.

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Section: Discussionmentioning

confidence: 99%

N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

Zhu

Lian

Chen

et al. 2022

Preprint

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“… 69 Furthermore, ALKBH5 could also regulated OS cells proliferation, apoptosis and cycle arrest by targeting selective signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signalling 3 (SOCS3). 70 In OA, the most studied m6A‐related proteins are METTL3, which promotes OA progression by regulating extracellular matrix (ECM) degradation and fibroblast‐like synoviocytes (FLS) senescence. Sang et al found that METTL3 overexpression regulated TIMPs and MMPs expression affecting the inflammatory response and ECM degradation.…”

Section: M6a Modificationmentioning

confidence: 99%

Novel insights into the interaction between N6‐methyladenosine methylation and noncoding RNAs in musculoskeletal disorders

et al. 2022

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Background: Musculoskeletal disorder (MSD) are a class of inflammatory and degener-ative diseases, but the precise molecular mechanisms are still poorly understood. Noncoding RNA (ncRNA) N6-methyladenosine (m6A) modification plays an essential role in the pathophysiological process of MSD. This review summarized the interaction between m6A RNA methylation and ncRNAs in the molecular regulatory mechanism of MSD. It provides a new perspective for the pathophysiological mechanism and ncRNA m6A targeted therapy of MSD.Methods: A comprehensive search of databases was conducted with musculoskeletal disorders, noncoding RNA, N6-methyladenosine, intervertebral disc degeneration, osteoporosis, osteosarcoma, osteoarthritis, skeletal muscle, bone, and cartilage as the key-words. Then, summarized all the relevant articles.Results: Intervertebral disc degeneration (IDD), osteoporosis (OP), osteosarcoma (OS), and osteoarthritis (OA) are common MSDs that affect muscle, bone, cartilage, and joint, leading to limited movement, pain, and disability. However, the precise pathogenesis remains unclear, and no effective treatment and drug is available at present. Numerous studies confirmed that the mutual regulation between m6A and ncRNAs (i.e., microRNAs, long ncRNAs, and circular RNAs) was found in MSD, m6A modification can regulate ncRNAs, and ncRNAs can also target m6A regulators. ncRNA m6A modification plays an essential role in the pathophysiological process of MSDs by regulating the homeostasis of skeletal muscle, bone, and cartilage.Conclusion: m6A interacts with ncRNAs to regulate multiple biological processes and plays important roles in IDD, OP, OS, and OA. These studies provide new insights into the pathophysiological mechanism of MSD and targeting m6A-modified ncRNAs may be a promising therapy approach.

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“…With the advances in technology, increasing evidence showed that m 6 A modification plays crucial roles in the occurrence/progression of various disease ( 7–12 ). Recent literature indicated that m 6 A modification could be a new molecular tool to understand the occurrence and progression of diseases, which is regulated by many m 6 A regulators ( 24 , 88 , 89 ), and an increasing number of m 6 A regulators and their corresponding target gene were identified to have clinical implications in either diagnosis/prognosis or therapy for various diseases ( 24 , 90 , 91 ).…”

Section: Factual Content and Data Retrievalmentioning

confidence: 99%

M6AREG: m6A-centered regulation of disease development and drug response

Liu

Chen

Zhang

et al. 2022

Nucleic Acids Research

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As the most prevalent internal modification in eukaryotic RNAs, N6-methyladenosine (m6A) has been discovered to play an essential role in cellular proliferation, metabolic homeostasis, embryonic development, etc. With the rapid accumulation of research interest in m6A, its crucial roles in the regulations of disease development and drug response are gaining more and more attention. Thus, a database offering such valuable data on m6A-centered regulation is greatly needed; however, no such database is as yet available. Herein, a new database named ‘M6AREG’ is developed to (i) systematically cover, for the first time, data on the effects of m6A-centered regulation on both disease development and drug response, (ii) explicitly describe the molecular mechanism underlying each type of regulation and (iii) fully reference the collected data by cross-linking to existing databases. Since the accumulated data are valuable for researchers in diverse disciplines (such as pathology and pathophysiology, clinical laboratory diagnostics, medicinal biochemistry and drug design), M6AREG is expected to have many implications for the future conduct of m6A-based regulation studies. It is currently accessible by all users at: https://idrblab.org/m6areg/

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ALKBH5 regulates STAT3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6A-YTHDF2-dependent manner

Cited by 45 publications

References 50 publications

N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

Novel insights into the interaction between N6‐methyladenosine methylation and noncoding RNAs in musculoskeletal disorders

M6AREG: m6A-centered regulation of disease development and drug response

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