SUMOylation of TARBP2 regulates miRNA/siRNA efficiency

Chen, Cheng; Zhu, Changhong; Huang, Jian; Zhao, Xian; Deng, Rong; Zhang, Hailong; Dou, Jinzhuo; Chen, Qin; Xu, Ming; Han, Yuanfei; Wang, Yanli; Yu, Jianxiu

doi:10.1038/ncomms9899

Cited by 31 publications

(46 citation statements)

References 71 publications

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“…Thus, we focused on SUMO1 modification of METTL3 in the following studies. Since Sentrin/SUMO-specific protease 1 (Senp1) is an SUMO1 modification-specific protease (19), we wondered whether Senp1 can remove the SUMO1 modification. Indeed, the significantly increased SUMOylation of exogenous METTL3 by Ubc9 was greatly weakened by cotransfection of the plasmid Senp1 (Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

“…It is becoming increasingly clear that SUMO modification plays important roles in the development and progression of cancer (19–21,26–28,48–50). Growing evidences have also revealed that key enzymes for m 6 A demethylation such as ALKBH5 (8,39) and FTO (38) have important regulatory roles in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…METTL3 SUMOylation was analysed in HEK-293T cells by the method of in vivo SUMOylation assay using Ni 2+ -NTA beads as previously described by our lab (19–21,26–28). …”

Section: Methodsmentioning

confidence: 99%

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SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

Hou

Zhang

et al. 2018

Nucleic Acids Research

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The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K177, K211, K212 and K215, which can be reduced by an SUMO1-specific protease SENP1. SUMOylation of METTL3 does not alter its stability, localization and interaction with METTL14 and WTAP, but significantly represses its m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs. Consistently with this, the abundance of m6A in mRNAs is increased with re-expression of the mutant METTL3-4KR compared to that of wild-type METTL3 in human non-small cell lung carcinoma (NSCLC) cell line H1299-shMETTL3, in which endogenous METTL3 was knockdown. The alternation of m6A in mRNAs and subsequently change of gene expression profiles, which are mediated by SUMOylation of METTL3, may directly influence the soft-agar colony formation and xenografted tumor growth of H1299 cells. Our results uncover an important mechanism for SUMOylation of METTL3 regulating its m6A RNA methyltransferase activity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

Hou

Zhang

et al. 2018

Nucleic Acids Research

Self Cite

232

176

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“…However, the E3 ligase of TARBP2 and ubiquitination levels need to be determined for further investigation in cancer. Supporting this concept, the SUMOylation of TARBP2 stabilizes TARBP2 protein expression through reducing its ubiquitination to suppress tumor progression, indicating that the ubiquitination of TARBP2 is essential for cancer progression (Chen et al ., ). Additionally, autophagy facilitates sorafenib resistance in HCC cells (Liu et al ., ; Zhai et al ., ), suggesting that inhibition of autophagy resensitizes HCC cells to sorafenib treatment through blocking the degradation of TARBP2.…”

Section: Discussionmentioning

confidence: 97%

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

Lai

Hong

et al. 2019

Molecular Oncology

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Hepatocellular carcinoma ( HCC ) is a lethal human malignancy and a leading cause of cancer‐related death worldwide. Patients with HCC are often diagnosed at an advanced stage, and the prognosis is usually poor. The multikinase inhibitor sorafenib is the first‐line treatment for patients with advanced HCC . However, cases of primary or acquired resistance to sorafenib have gradually increased, leading to a predicament in HCC therapy. Thus, it is critical to investigate the mechanism underlying sorafenib resistance. Transactivation response element RNA ‐binding protein 2 (TARBP2) is a multifaceted mi RNA biogenesis factor that regulates cancer stem cell ( CSC ) properties. The tumorigenicity and drug resistance of cancer cells are often enhanced due to the acquisition of CSC features. However, the role of TARBP 2 in sorafenib resistance in HCC remains unknown. Our results demonstrate that TARBP 2 is significantly downregulated in sorafenib‐resistant HCC cells. The TARBP 2 protein was destabilized through autophagic–lysosomal proteolysis, thereby stabilizing the expression of the CSC marker protein Nanog, which facilitates sorafenib resistance in HCC cells. In summary, here we reveal a novel mi RNA ‐independent role of TARBP 2 in regulating sorafenib resistance in HCC cells.

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“…It has been reported that AGO2 plays a key role in the RNA interference pathway and that other RNA modulators, such as TARBP2, may affect this and other pathways [49,50]. Thus the use of the AGO2 immunoblot alone was not sufficient in our study to gain a real measure of RNAi processing.…”

Section: Discussionmentioning

confidence: 85%

MicroRNA Quantitation During Dendritic Cell Endocytosis Using Imaging Flow Cytometry: Key Factors and Requirements

Tong

Zhu

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNA (miRNA)-induced suppression of dendritic cells (DCs) has been implicated in many diseases. Therefore, accurate monitoring of miRNA endocytosis by DCs is important for understanding the role of miRNAs in many diseases. Recently, a method for measuring the co-localization of Argonaute 2 (AGO2)-associated miRNAs on laser-scanning confocal microscopy method was proposed to localize the miRNAs. But its definition was limited by the number of observed cells through its accuracy. Methods: In this study, a method based on imaging flow cytometry was developed to localize miR-590-5p with fluorescent probes in DCs. miR-590-5p proven to play an important role in tumor immunity. This method enabled the quantification, visualization and localization of the fluorescence intensity in 30,000 individual cells. Results: Using this method, the DCs with different endocytotic ability were distinguished. The behaviour of miR-590-5p during endocytosis under the stimulation of tumor antigen in DCs was observed, binding to its cognate target mRNA and degradation in DCs. Conclusion: This method based on imaging flow cytometry provide an additional method to study miRNA processing in DCs, which makes it a valuable addition to existing miRNA research techniques.

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SUMOylation of TARBP2 regulates miRNA/siRNA efficiency

Cited by 31 publications

References 71 publications

SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

MicroRNA Quantitation During Dendritic Cell Endocytosis Using Imaging Flow Cytometry: Key Factors and Requirements

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