Stabilization of IGF2BP1 by USP10 promotes breast cancer metastasis via CPT1A in an m6A-dependent manner

Shi, Jiajun; Yin, Xia; Ye, Jiahui; Gao, Sheng-Qing; Chen, Chen; Yang, Yaxuan; Wu, Baojuan; Fu, Yuping; Zhang, Hongmei; Wang, Zhangding; Wang, Bo; Zhu, Yun; Wu, Hongyan; Yao, Yongzhong; Xu, Guifang; Wang, Qiang; Wang, Shouyu; Zhang, Weijie

doi:10.7150/ijbs.76798

Cited by 31 publications

(9 citation statements)

References 79 publications

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“…Studies have shown that there is a crosstalk between RNA m 6 A modification and protein ubiquitination (Shi et al 2023 ; Zhang et al 2022b ), but the relationship between RNA m 6 A modification and protein ubiquitination is not clear. In our study, we found that m 6 A was located upstream of ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Xu,

Zhao,

Feng

et al. 2024

Cell Biol Toxicol

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Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m6A methylation levels on the 3’UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6A readers YTHDF1 and IGF2BP1 are responsible for m6A-mediated increase in p21 mRNA stability. Meanwhile, 3’UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6A hypermethylated, and another m6A reader YTHDF2 binds to the m6A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases. Graphical abstract DON inhibits the proliferation of HT-22 cells. RNA m6A hypermethylation on the transcript of p21 enhances the mRNA stability in a YTHDF1- and IGF2BP1-dependent manner, which leads to the upregulation of p21. RNA m6A hypermethylation on the transcript of TRIM21 decreases the mRNA stability in a YTHDF2-dependent manner, which contributes to prevent p21 ubiquitin-mediated degradation. High expression of p21 contributes to inhibit cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Xu,

Zhao,

Feng

et al. 2024

Cell Biol Toxicol

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“…Carnitine palmitoyltransferase (CPT) facilitates the transport of long-chain fatty acids across the mitochondrial membrane, where they undergo β-oxidation to generate acetyl-CoA and produce ATP (Figure 1C). In breast cancer, the stabilisation of CPT1A mRNA by IGF2BP1 leads to an increase in cell migration and invasion [90]. The inhibition of CPT1A expression decreases proliferation and tumorigenicity in melanoma cells [91].…”

Section: Altered Fatty Acid Oxidationmentioning

confidence: 99%

Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors

Gupta,

Das,

Taneja

2024

Cancers

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Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.

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“…Functionally, IGF2BPs mainly recognizes and binds mRNA through KH domain, thus enhancing the stability of m6A-modified mRNA and improving the translation efficiency of mRNA, thus regulating various physiological and pathological functions. IGF2BP1 has been identified to play an important role in the regulation of mRNA targets such as CPT1A, E2F1, PEG10, c-MYC, and CCL5 in an m6Adependent manner [13][14][15][16]. Zhou et al reported that METTL3 promotes osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs) through IGF2BP1-mediated Runx2 mRNA stabilization to regulate osteogenic responses [17].…”

Section: Ivyspringmentioning

confidence: 99%

METTL3 Promotes Osteogenic Differentiation of Human Periodontal Ligament Stem Cells through IGF2BP1-Mediated Regulation of Runx2 Stability

Sun,

Meng,

Piao

et al. 2024

Int. J. Med. Sci.

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N6-Methyladenosine (m 6 A) has been reported to play a dynamic role in osteoporosis and bone metabolism. However, whether m 6 A is involved in the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) remains unclear. Here, we found that methyltransferase-like 3 (METTL3) was up-regulated synchronously with m 6 A during the osteogenic differentiation of hPDLSCs. Functionally, lentivirus-mediated knockdown of METTL3 in hPDLSCs impaired osteogenic potential. Mechanistic analysis further showed that METTL3 knockdown decreased m 6 A methylation and reduced IGF2BP1-mediated stability of runt-related transcription factor 2 (Runx2) mRNA, which in turn inhibited osteogenic differentiation. Therefore, METTL3-based m 6 A modification favored osteogenic differentiation of hPDLSCs through IGF2BP1-mediated Runx2 mRNA stability. Our study shed light on the critical roles of m 6 A on regulation of osteogenic differentiation in hPDLSCs and served novel therapeutic approaches in vital periodontitis therapy.

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Stabilization of IGF2BP1 by USP10 promotes breast cancer metastasis via CPT1A in an m6A-dependent manner

Cited by 31 publications

References 79 publications

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors

METTL3 Promotes Osteogenic Differentiation of Human Periodontal Ligament Stem Cells through IGF2BP1-Mediated Regulation of Runx2 Stability

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