SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

González-Rodríguez, Patricia; Engskog-Vlachos, Pinelopi; Zhang, Hanzhao; Murgoci, Adriana-Natalia; Zerdes, Ioannis; Joseph, Bertrand

doi:10.1038/s41419-020-2266-x

Cited by 38 publications

(33 citation statements)

References 57 publications

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“…Also, SETD2 acts as a regulator of N6-methyladenosine RNA methylation and modi ers in cancer(38).SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints (39). Furthermore, SETD2 regulates cancer development (40).Dual chromatin and cytoskeletal was remodeled by SETD2 (41).Interestingly, SETD2 mutation suppress autophagy via regulation of ATG12 (42).…”

Section: Discussionmentioning

confidence: 99%

Mutant MEG3 Enhances the Activity of Telomerase by Increasing DNA Damage Repair in Human Liver Cancer Stem Cells

Song

Xie

Qin

et al. 2021

Preprint

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Background: Long noncoding RNAs have recently considered as central regulators in diverse biological processes and emerged as vital players controlling tumorigenesis. Although wild MEG3 acts as a suppressor in several cancers, the function of mutant MEG3 is also unclear during tumorigenesis.Methods: Lentivalus infection,RT-PCR,Western blotting and tumorigenesis test in vitro and in vivo were performed.Results: our results suggest that mutant MEG3 promotes the growth of human liver cancer stem cells in vivo and in vitro.Mechanistically, our results show that mutant MEG3 enhances acetylation modification of HistoneH4 on K16.Then, mutant MEG3 enhances the expression of SETD2 dependent on H4K16Ac.Moreover, mutant MEG3 increases the DNA damage repair through SETD2.Ultimately, mutant MEG3 increases the telomeras activity dependent on DNA damage repair.Strikingly,TERT determines the cancerous function of mutant MEG3 in liver cancer stem cells. Therefore, we shed light on the fact that targeting mutant MEG3 could be a viable approach for cancer treatment.Conclusions: these observations will play an important role in finding effective tumor treatment targets.

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Section: Discussionmentioning

confidence: 99%

Mutant MEG3 Enhances the Activity of Telomerase by Increasing DNA Damage Repair in Human Liver Cancer Stem Cells

Song

Xie

Qin

et al. 2021

Preprint

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“…Recently, the SETD2 gene has been shown to directly regulate the transcription of a subset of genes via cooperation with the transcription factor TP53 and contribute to further inactivation of TP53 -mediated checkpoint control ( Carvalho et al, 2014 ; Xie et al, 2008 ). In addition, SETD2 mutations have been linked to poor clinical prognosis in various tumors, such as in renal clear cell carcinoma and AML ( Wang et al, 2019 ; González-Rodríguez et al, 2020 ). Notably, SETD2 deficiency has been found to impair HSC self-renewal and induce MDS transformation in a conditional SETD2 -knockout mouse model ( Zhang et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…As a transcriptional regulator, SETD2 has been shown to participate in diverse biological processes including alternative splicing, transcriptional elongation, DNA repair, and embryonic differentiation ( Venkatesh et al, 2012 ; Li et al, 2013 ; Neri et al, 2017 ). SETD2 mutations are often present and predict poor survival in several types of leukemia as well as various solid tumors ( Kandoth et al, 2013 ; Mar et al, 2014 ; Zhu et al, 2014 ; González-Rodríguez et al, 2020 ). A recent study confirms that loss-of-function SETD2 mutations facilitate the initiation of leukemia and impair DNA damage recognition, leading to resistance to therapy ( Sheng et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

SET Domain Containing 2 Deficiency in Myelodysplastic Syndrome

Peng

Luo

et al. 2020

Front. Genet.

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Recent studies have shown that myelodysplastic syndrome’s (MDS) progression to acute myeloid leukemia (AML) is associated with gene mutations. SET domain containing 2 ( SETD2 ) variants were reported as a risk factor of poor prognosis in patients with AML. However, little is known about the potential contribution of the SETD2 gene in MDS. In this study, we investigated the roles of SETD2 gene mutations/variants on clinical features and prognosis in patients with MDS. A 43-gene panel was used for next-generation sequencing in 203 patients with primary MDS, and then the effects of SETD2 mutation on Wnt/β-catenin signaling was investigated during the different stages of MDS. At a median follow up of 33 months, 65 (32.0%) deaths and 94 (46.3%) leukemic transformations were recorded. The most frequent mutations/variants included TET2 , DNMT3A , and ASXL1 mutations/variants. 37 patients had SETD2 gene mutations/variants, and these patients exhibited a significantly increased frequency of TP53 mutations. Multivariate survival analyses indicated that SETD2 mutations/variants were closely associated with overall survival (OS), and they were identified as risk factors for progression-free survival (PFS), especially with low expression of SETD2 gene. Further, we found that SETD2 loss could promote MDS progression via upregulation DVL3 mRNA level in BM cells and it could also cause genomic instability. Secondary mutations, such as TP53 and FLT3 mutations, were acquired at the time of progression to AML. In conclusion, we showed that SETD2 deficiency was associated with poor outcomes in patients with MDS. Moreover, SETD2 deficiency may upregulate DVL3 expression and modulate genomic stability that caused AML transformation.

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“…ATG9A supplies PtdIns4P to the autophagosome initiation site (56). SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12 (57).…”

Section: Discussionmentioning

confidence: 99%

miR155 Enhances Autophagy by Reducing MBD5 and METTL3 in Human Liver Cancer Stem Cells

Lu¹,

Chen²,

Xin³

et al. 2020

Preprint

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Background: miR-155 is a widely reported carcinogenic miRNA, with up-regulated expression in a variety of human cancers. Methods: Liver cancer stem cells were isolated from Huh7 cells; gene infection, RT-PCR, Western blotting and tumorigenesis test in vitro and in vivo were performed to analyze the signaling pathway. Results: we demonstrate that miR-155 inhibits the expression of MBD5 and METTL3 , reducing the expression of DNMT1. In particular, miR155 inhibits the interaction between MBD5 and DNMT1, thereby inhibiting the binding capacity among MBD5, DNMT1 and IGFII (H19 ICR, IGFII DMR, IGFII Enhancer) DNA, inhibiting IGFII DNA methylation modification. Importantly, miR-155 promotes the formation of DNA loops in the IGFII DNA region (H19 ICR-IGFII Enhancer, IGFII DMR-IGFII Enhancer). Therefore, miR155 promotes the binding ability of H19-pre miR675 to histone methyltransferases SUV39h2 dependent on the H19 ICR-IGFII enhancer DNA loop and enhances the methylation modification of histone H3 on the ninth lysine . Then, the binding ability of RNA polII to P300 was enhanced by the formation of H3K9me2-RNA polII-P300 complex. Furthermore, miR155 promotes the binding ability of the RNA PolII-P300 complex to the IGFII promoter dependent on the IGFII DMR-IGFII enhancer DNA loop and promotes the expression of IGFII. Further research shows that miR155 promotes the binding of IGFII to stemness factors and the loading of stemness factors into the promoter region of HGF, which promotes the expression of hepatocyte growth factor HGF. In particular, miR155 promotes the expression of albumin gene (ALB) via HGF-c-MET, and then promotes the Sirt1 expression through ALB. Strikingly, miR155 promotes the autophagy dependent on acetylase Sirt1,including that miR155 promotes LC3 activation dependent on acetylase sirt1 and enhances binding capacity of LC3 to TP53INP2 / DOR, ATG4, ATG3 and ATG7, and the binding ability of the interaction between ATG5, ATG12, ATG6L1, ATG9. More meaningfully, miR155 enhances the ability of H-Ras to bind to the autophagosomes Beclin1, vps34, vps5, Uvrage, bif1, Lamp1, Lamp2, Lamp3, Rubicon, Rab24 dependent on autophagy, thereby enhancing the expression of H-Ras. Furthermore, miR155 enhances the expression of pRaf1, pMEK1 / 2, pERK1 / 2, pElK, pJak, Jun, pAKT, pmTOR, P70S6K, 4E-BP1, SGK1, C-myc dependent on H-Ras.Finally, miR-155 promotes the malignant growth of human liver cancer stem cells mediated by H-Ras.Conclusions: these results provide a valuable theoretical basis for therapeutic targets of liver cancer based on miR-155.

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SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

Cited by 38 publications

References 57 publications

Mutant MEG3 Enhances the Activity of Telomerase by Increasing DNA Damage Repair in Human Liver Cancer Stem Cells

Mutant MEG3 Enhances the Activity of Telomerase by Increasing DNA Damage Repair in Human Liver Cancer Stem Cells

SET Domain Containing 2 Deficiency in Myelodysplastic Syndrome

miR155 Enhances Autophagy by Reducing MBD5 and METTL3 in Human Liver Cancer Stem Cells

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