TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

Zhou, Sha; Peng, Jianhong; Xiao, Liuniu; Chun, Zhou; Yu, Fang; Ou, Qingjian; Qin, Jiayi; Liu, Mengzhong; Pan, Zhizhong; Hou, Zhenlin

doi:10.1038/s41419-021-03734-4

Cited by 33 publications

(26 citation statements)

References 42 publications

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“…For example, by regulating mitotic checkpoints and chromosome stability, TIF1 γ inhibits tumor progression [ 38 ]. Recently, epigenetic regulation was shown to play a vital role in the occurrence and development of tumors, such as regulating tumor resistance, proliferation, metastasis, and epithelial-mesenchymal transition [ 39 – 44 ]. Interestingly, prognostic model based on epigenetic regulation was constructed to predict patient prognosis, such as a prognostic model based on nine ferroptosis-related genes ( ALOX15 , CISD1 , CS , GCLC , GPX4 , SLC7A11 , EMC2 , G6PD , and ACSF2 ) that could predict the prognosis of breast cancer [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

An Immune-Related Long Noncoding RNA Signature as a Prognostic Biomarker for Human Endometrial Cancer

Wang

Liu

Zhang

et al. 2021

Journal of Oncology

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Background. Endometrial cancer is among the most common malignant tumors threatening the health of women. Recently, immunity and long noncoding RNA (lncRNA) have been widely examined in oncology and shown to play important roles in oncology. Here, we searched for immune-related lncRNAs as prognostic biomarkers to predict the outcome of patients with endometrial cancer. Methods. RNA sequencing data for 575 endometrial cancer samples and immune-related genes were downloaded from The Cancer Genome Atlas (TCGA) database and gene set enrichment analysis (GSEA) gene sets, respectively. Immune-related lncRNAs showing a coexpression relationship with immune-related genes were obtained, and Cox regression analysis was performed to construct the prognostic model. Survival, independent prognostic, and clinical correlation analyses were performed to evaluate the prognostic model. Immune infiltration of endometrial cancer samples was also evaluated. Functional annotation of 12 immune-related lncRNAs was performed using GSEA software. Prognostic nomogram and survival analysis for independent prognostic risk factors were performed to evaluate the prognostic model and calculate the survival time based on the prognostic model. Results. Twelve immune-related lncRNAs (ELN-AS1, AC103563.7, PCAT19, AF131215.5, LINC01871, AC084117.1, NRAV, SCARNA9, AL049539.1, POC1B-AS1, AC108134.4, and AC019080.5) were obtained, and a prognostic model was constructed. The survival rate in the high-risk group was significantly lower than that in the low-risk group. Patient age, pathological grade, the International Federation of Gynecology and Obstetrics (FIGO) stage, and risk status were the risk factors. The 12 immune-related lncRNAs correlated with patient age, pathological grade, and FIGO stage. Principal component analysis and functional annotation showed that the high-risk and low-risk groups separated better, and the immune status of the high-risk and low-risk groups differed. Nomogram and receiver operating characteristic (ROC) curves effectively predicted the prognosis of endometrial cancer. Additionally, age, pathological grade, FIGO stage, and risk status were all related to patient survival. Conclusion. We identified 12 immune-related lncRNAs affecting the prognosis of endometrial cancer, which may be useful as therapeutic targets and molecular biomarkers.

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Section: Discussionmentioning

confidence: 99%

An Immune-Related Long Noncoding RNA Signature as a Prognostic Biomarker for Human Endometrial Cancer

Wang

Liu

Zhang

et al. 2021

Journal of Oncology

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“…TRIM25, as a member of the E3 ubiquitination ligase family, has been reported to regulate the ubiquitination of various proteins. 37 Here, we showed that GADD45A might recruit TRIM25 and increase the total ubiquitination and degradation of ATP5A1. The biochemical link between GADD45A and ATP5A1 appears to be a critical pathogenic mechanism during the development of adipogenesis and skeletal muscle metabolic diseases.…”

Section: Discussionmentioning

confidence: 72%

Growth arrest and DNA damage‐inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha

Liu

Ling

et al. 2022

J cachexia sarcopenia muscle

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Background Skeletal muscle fat infiltration is a common feature during ageing, obesity and several myopathies associated with muscular dysfunction and sarcopenia. However, the regulatory mechanisms of intramuscular adipogenesis and strategies to reduce fat infiltration in muscle remain unclear. Here, we identified the growth arrest and DNA damage‐inducible alpha (GADD45A), a stress‐inducible histone folding protein, as a critical regulator of intramuscular fat (IMAT) infiltration. Methods To explore the role of GADD45A on IMAT infiltration and muscle regeneration, the gain or loss function of GADD45A in intramuscular preadipocytes was performed. The adipocyte‐specific GADD45A knock‐in (KI) mice and high IMAT‐infiltrated muscle model by glycerol injection (50 μL of 50% v/v GLY) were generated. RNA‐sequencing, histological changes, gene expression, lipid metabolism, mitochondrial function and the effect of dietary factor epigallocatechin‐3‐gallate (EGCG) treatment (100 mg/kg) on IMAT infiltration were studied. Results The unbiased transcriptomics data analysis indicated that GADD45A expression positively correlates with IMAT infiltration and muscle metabolic disorders in humans (correlation: young vs. aged people, Gadd45a and Cebpa, r2 = 0.20, P < 0.05) and animals (correlation: wild‐type [WT] vs. mdx mice, Gadd45a and Cebpa, r2 = 0.38, P < 0.05; NaCl vs. GLY mice, Gadd45a and Adipoq/Fabp4, r2 = 0.80/0.71, both P < 0.0001). In vitro, GADD45A overexpression promotes intramuscular preadipocyte adipogenesis, upregulating the expression of adipogenic genes (Ppara: +47%, Adipoq: +28%, P < 0.001; Cebpa: +135%, Fabp4: +16%, P < 0.01; Pparg: +66%, Leptin: +77%, P < 0.05). GADD45A knockdown robustly decreased lipid accumulation (Pparg: −57%, Adipoq: −35%, P < 0.001; Fabp4: −37%, P < 0.01; Leptin: −28%, P < 0.05). GADD45A KI mice exhibit inhibited skeletal muscle regeneration (myofibres: −40%, P < 0.01) and enhanced IMAT infiltration (adipocytes: +20%, P < 0.05). These KI mice have impaired exercise endurance and mitochondrial function. Mechanistically, GADD45A affects ATP synthase F1 subunit alpha (ATP5A1) ubiquitination degradation (ubiquitinated ATP5A1, P < 0.001) by recruiting the E3 ubiquitin ligase TRIM25, which decreases ATP synthesis (ATP production: −23%, P < 0.01) and inactivates the cAMP/PKA/LKB1 signalling pathway (cAMP: −36%, P < 0.01; decreased phospho‐PKA and phospho‐LKB1 protein content, P < 0.01). The dietary factor EGCG can protect against muscle fat infiltration (triglyceride: −64%, P < 0.05) via downregulating GADD45A (decreased GADD45A protein content, P < 0.001). Conclusions Our findings reveal a crucial role of GADD45A in regulating muscle repair and fat infiltration and suggest that inhibition of GADD45A by EGCG might be a potential strategy to combat fat infiltration and its associated muscle dysfunction.

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“…Similarly, in bladder cancer cells, overexpressed RITA1 induced degradation of RBPJ by recruiting the E3 ligase TRIM25 [ 80 ]. In this case, however, RBPJ proteolysis appeared to increase malignancy, which may apply for other cancer types linked to TRIM25 activity as well [ 80 , 81 , 82 , 83 ].…”

Section: Discussionmentioning

confidence: 76%

The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation

Fechner

Ketelhut

Maier

et al. 2022

IJMS

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The primary role of Notch is to specify cellular identities, whereby the cells respond to amazingly small changes in Notch signalling activity. Hence, dosage of Notch components is crucial to regulation. Central to Notch signal transduction are CSL proteins: together with respective cofactors, they mediate the activation or the silencing of Notch target genes. CSL proteins are extremely similar amongst species regarding sequence and structure. We noticed that the fly homologue suppressor of hairless (Su(H)) is stabilised in transcription complexes. Using specific transgenic fly lines and HeLa RBPJKO cells we provide evidence that Su(H) is subjected to proteasomal degradation with a half-life of about two hours if not protected by binding to co-repressor hairless or co-activator Notch. Moreover, Su(H) stability is controlled by MAPK-dependent phosphorylation, matching earlier data for RBPJ in human cells. The homologous murine and human RBPJ proteins, however, are largely resistant to degradation in our system. Mutating presumptive protein contact sites, however, sensitised RBPJ for proteolysis. Overall, our data highlight the similarities in the regulation of CSL protein stability across species and imply that turnover of CSL proteins may be a conserved means of regulating Notch signalling output directly at the level of transcription.

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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

Cited by 33 publications

References 42 publications

An Immune-Related Long Noncoding RNA Signature as a Prognostic Biomarker for Human Endometrial Cancer

An Immune-Related Long Noncoding RNA Signature as a Prognostic Biomarker for Human Endometrial Cancer

Growth arrest and DNA damage‐inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha

The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation

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