Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma

Yang, Hao; Zhu, Rongxuan; Zhao, Xiaoping; Liu, Liu; Zhou, Zhaoli; Zhao, Li; Liang, Beibei; Ma, Wenjing; Zhao, Jian; Li, Jianjun; Huang, Gang

doi:10.1038/s41388-019-0764-z

Cited by 61 publications

(37 citation statements)

References 44 publications

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“…hnRNPA1 regulates alternative splicing of interferon regulatory factor 3 and affects immunomodulatory functions in human non-small cell lung cancer cells [33]. hnRNPA1 plays a crucial role in regulating cell proliferation, invasiveness, metabolism, and immortalization in multiple tumors such as hepatocellular carcinoma, prostate cancer, and oral squamous cell cancer [22,[34][35][36]. In the present study, silencing hnRNPA1 antagonized the enhancement of LUAD cell growth, colony formation, migration, and invasion induced by ESCO2 overexpression.…”

Section: Discussionsupporting

confidence: 54%

ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

Zhu

Shi³

et al. 2020

Preprint

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Background: Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown. Methods: Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studied using cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD. Results: We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation. Conclusions: Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

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Section: Discussionsupporting

confidence: 54%

ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

Zhu

Shi³

et al. 2020

Preprint

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“…Other post-translational modifications, such as acetylation and ubiquitination, are important modulators of splicing factors activity. For example, the hyper-acetylation of hnRNP A1 induced by high glucose levels in hepatocellular carcinoma cells promotes the production of the PKM2 variant and consequent enhancement of glucose metabolism as well as transcription of genes responsible for cell proliferation and growth, such as GLUT1, LDHA, PDK1, CCND1, and MYC (Yang et al, 2019). In addition, the hyper-acetylation of SRSF5 by Tip60 acetyltransferase causes the production of the CCAR1 isoform S, which favors tumor growth by promoting glucose consumption and acetyl-CoA production (Chen et al, 2018a).…”

Section: Deregulation Of the Splicing Machinery In Cancermentioning

confidence: 99%

The Role of RNA Splicing Factors in Cancer: Regulation of Viral and Human Gene Expression in Human Papillomavirus-Related Cervical Cancer

Cerasuolo

Buonaguro

Tornesello

2020

Front. Cell Dev. Biol.

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The spliceosomal complex components, together with the heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine/arginine-rich (SR) proteins, regulate the process of constitutive and alternative splicing, the latter leading to the production of mRNA isoforms coding multiple proteins from a single pre-mRNA molecule. The expression of splicing factors is frequently deregulated in different cancer types causing the generation of oncogenic proteins involved in cancer hallmarks. Cervical cancer is caused by persistent infection with oncogenic human papillomaviruses (HPVs) and constitutive expression of viral oncogenes. The aberrant activity of hnRNPs and SR proteins in cervical neoplasia has been shown to trigger the production of oncoproteins through the processing of pre-mRNA transcripts either derived from human genes or HPV genomes. Indeed, hnRNP and SR splicing factors have been shown to regulate the production of viral oncoprotein isoforms necessary for the completion of viral life cycle and for cell transformation. Target-therapy strategies against hnRNPs and SR proteins, causing simultaneous reduction of oncogenic factors and inhibition of HPV replication, are under development. In this review, we describe the current knowledge of the functional link between RNA splicing factors and deregulated cellular as well as viral RNA maturation in cervical cancer and the opportunity of new therapeutic strategies.

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“…HnRNPL is mainly located in the nucleus, but it can also exert effects in the cytoplasm via post-transcriptionally regulating lncRNA expression [ 60 , 61 ]. Additionally, the oncogenic transcription factor MYC can upregulate the mRNA levels of heteronuclear ribonucleoproteins (hnRNP) A1 and A2 in a variety of malignant tumors, and hnRNPs facilitate the synthesis of M-type pyruvate kinase (PKM2), thus strengthening the Warburg effect [ 24 , 25 , 62 – 64 ]. In gastric cancer cells, the PI3K/AKT/NF-κB and METTL3/ZMYM1/E-cadherin signaling pathways can promote the transcription of RBP human antigen R (HuR), which is engaged in increased cell growth and anti-apoptotic capability [ 28 , 30 , 65 ].…”

Section: Introductionmentioning

confidence: 99%

RNA-binding proteins in tumor progression

et al. 2020

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RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.

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Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma

Cited by 61 publications

References 44 publications

ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

The Role of RNA Splicing Factors in Cancer: Regulation of Viral and Human Gene Expression in Human Papillomavirus-Related Cervical Cancer

RNA-binding proteins in tumor progression

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