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METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis.

ABSTRACT: The development of osteoporosis is often accompanied by autophagy disturbance, which also causes new osteoblast defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) is the main enzyme for N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, and it has been implicated in many bioprocesses. Herein, we demonstrate that METTL14 plays a critical role in autophagy induction and hinders osteoporosis process whose expression is decreased both in human osteoporosis bone tissue and ovariectomy (OVX) mice. In vivo, METTL14+/- knockdown mice exhibit elevated bone loss and impaired autophagy similar to the OVX mice, while overexpression of METTL14 significantly promotes bone formation and inhibits the progression of osteoporosis caused by OVX surgery. In vitro, METTL14 overexpression significantly enhances the osteogenic differentiation ability of BMSCs through regulating the expression of beclin-1 depending on m6A modification and inducing autophagy; the opposite is true with METTL14 silencing. Subsequently, m6A-binding proteins IGF2BP1/2/3 recognize m6A-methylated beclin-1 mRNA and promote its translation via mediating RNA stabilization. Furthermore, METTL14 negatively regulates osteoclast differentiation. Collectively, our study reveals the METTL14/IGF2BPs/beclin-1 signal axis in BMSCs osteogenic differentiation and highlights the critical roles of METTL14-mediated m6A modification in osteoporosis.

SUBMITTER: He M

PROVIDER: S-EPMC9492283 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis.

He Mingyu M Lei Hong H He Xiaoqi X Liu Ying Y Wang Ao A Ren Zijing Z Liu Xiaoyan X Yan Gege G Wang Wenbo W Wang Yang Y Li Guanghui G Wang Tong T Pu Jiaying J Shen Zhihua Z Wang Yanquan Y Xie Jiajie J Du Weijie W Yuan Ye Y Yang Lei L

Stem cells translational medicine 20220901 9

The development of osteoporosis is often accompanied by autophagy disturbance, which also causes new osteoblast defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) is the main enzyme for N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, and it has been implicated in many bioprocesses. Herein, we demonstrate that METTL14 plays a critical role i ...[more]

PMID: 35980318

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Project description:BackgroundThe Jumonji domain-containing protein 6 (JMJD6), a histone arginine demethylase, is known to have a multifaceted and significant role on cancer progression. However, the specific function and mechanism of JMJD6 in non-small cell lung cancer (NSCLC) have yet to be fully elucidated.MethodsThe elevated expression of JMJD6 in lung cancer tissues was confirmed through a combination of bioinformatics and immunohistochemical analysis. Utilizing lung cancer cell lines H460, H157, A549, and H1299, we further investigated the impact of JMJD6 on various cellular processes such as ferroptosis, proliferation, migration, and invasion both in vivo and in vitro. The acetylation of JMJD6 was characterized using immunoprecipitation, co-immunoprecipitation, GST pull down, and immunofluorescence techniques. The regulatory role of JMJD6 acetylation in ferroptosis was assessed by measuring levels of ROS, MDA, and JC-1. WB, qRT-PCR, ChIP and MeRIP techniques were employed to investigate the relationship between the JMJD6 acetylation/METTL14/m6A/SLC3A2 axis.ResultsThis study revealed elevated levels of JMJD6 in tumor tissue, with high expression correlating strongly with advanced clinical stage in lung cancer patients, and identified JMJD6 as a significantly poor prognostic factor for lung cancer. Functional experiments verified that ectopic overexpression of JMJD6 enhanced the proliferation and migratory capacities of lung cancer cells, while JMJD6 knockdown showed opposite effects. We further find that JMJD6 functions as a negative modulator in regulating ferroptosis process. Mechanistically, JMJD6 affects METTL14 expression in an arginine demethylase dependent manner, and mediates m6A modification of SLC3A2 to regulate its expression level, thereby affecting the sensitivity of lung cancer cells to ferroptosis. Besides, our findings indicate that acetyltransferase p300/CBP associated factor (PCAF) interacts with and acetylates JMJD6 at lysine 375. Acetylation weakens the activity of JMJD6 demethylase, thereby enhancing METTL14 expression and affecting its mediated m6A modification to regulate SLC3A2. Acetylation at lysine 375 also augment the modulation of ferroptosis in lung cancer cells by JMJD6, consequently impeding the lung cancer progression.ConclusionTaken together, we elucidated the JMJD6 acetylation/METTL14/m6A/SLC3A2 axis as a key mediator of lung cancer progression, indicating that JMJD6 may serve as a potentially prognostic biomarker and therapeutic target for NSCLC.

Dataset Information

METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis.

Publications

METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis.

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