The splicing regulatory factor hnRNPU is a novel transcriptional target of c‐Myc in hepatocellular carcinoma

Zhang, Biao; Wang, Haiyang; Zhao, Dan; Wang, Dongxing; Zeng, Quan; Xi, Jiafei; Nan, Xue; He, Liyun; Zhou, Junnian; Pei, Xuetao; Yue, Wen

doi:10.1002/1873-3468.13943

Cited by 17 publications

(16 citation statements)

References 42 publications

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“…PALLD promotes pancreatic cancer cell invasion by promoting the invasive formation of tumor-associated fibroblasts [ 45 ]. HNRNPU is overexpressed in hepatocellular carcinoma (HCC) and promotes HCC occurrence and progression [ 46 , 47 ]. SERBP1 is a member of the RG/RGG family of RBPs, which is markedly overexpressed in glioblastoma and in prostate, ovarian, and liver cancer and is associated with poor outcomes [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

Wang

Kuang

Ding

et al. 2022

Cancers

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Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target.

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Section: Discussionmentioning

confidence: 99%

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

Wang

Kuang

Ding

et al. 2022

Cancers

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“…Furthermore, the actin-hnRNPU complex is a critical regulator of the beginning stage of transcriptional activation in eukaryotic cells (37). The hnRNPU and c-Myc regulatory loop have combined effects on the proliferation and self-renewal of HCC and promote its progression (38). Long non-coding RNA H19 also combines with hnRNPU and represses RNA polymerase II-mediated transcription by destroying the actin-hnRNPU complex (39).…”

Section: Discussionmentioning

confidence: 99%

“…We conducted a study on hnRNPU in the clinical diagnosis and prognosis of therapeutic efficacy of HCC and found that hnRNPU is a very significant gene. Zhang et al conducted an in-depth study on the molecular mechanism of this gene inside tumors and found that hnRNPU promotes tumor progression by regulating the proliferation of hepatocellular carcinoma cells through the downstream gene c-Myc (38), again suggesting that hnRNPU is a key gene. In our future study, we will explore the molecular mechanism of hnRNPU in HCC in depth.…”

Section: Discussionmentioning

confidence: 99%

Identification of heterogeneous nuclear ribonucleoprotein as a candidate biomarker for diagnosis and prognosis of hepatocellular carcinoma

Wang

et al. 2021

J Gastrointest Oncol

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Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high mortality rate. However, spliceosomal genes are still lacking in the diagnosis and prognosis of HCC.Methods: Identification of differentially expressed genes (DEGs) was performed using the limma package in R software. Modules highly related to HCC were obtained by weighted gene co-expression network analysis (WGCNA), and the module genes were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The biomarker for diagnosing HCC was determined by receiver operating characteristic (ROC) curve analysis, and the effect of the biomarker in the diagnosis of HCC was evaluated by performing five-fold cross-validation with logistic regression. HCC specimens from preoperatively treated patients were tested for biomarker by real-time quantitative polymerase chain reaction (RT-qPCR).Kaplan-Meier analysis was used to assess the relationship between biomarker and patient survival. The role of biomarker was evaluated using ESTIMATE analysis in the tumor microenvironment.Results: In this study, 389 DEGs were screened out from three Gene Expression Omnibus (GEO) datasets.We also found that the turquoise module of 123 genes from The Cancer Genome Atlas (TCGA) data was the key module with the highest correlation with HCC traits. Then, 123 genes were analyzed using the KEGG enrichment pathway, and eight genes were found to be most significantly related to the spliceosome pathway. We selected 8 genes and 389 DEGs shared genes, and finally got the only gene, heterogeneous nuclear ribonucleoprotein (hnRNPU). The high expression of hnRNPU was associated with poor prognosis of HCC, and hnRNPU was a biomarker for diagnosing HCC. In the tissues of patients with excellent HCC treatment hnRNPU messenger RNA (mRNA) was lower than in the tissues of patients with poor HCC treatment. High expression of hnRNPU was significantly increased in HCC patients with low stromal (P<0.05), low immune (P<0.05), and low estimation scores (P<0.05), and with high tumor purity (P<0.05) and high malignant progression (P<0.05) of the HCC. Conclusions:The hnRNPU gene identified in this study may become a new biomarker for the diagnosis and prognosis of HCC.

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“…It has been recently reported that overexpression of GAS7 affects stabilization of b-catenin protein via sequestering heterogeneous nuclear ribonucleoprotein U (HNRNPU) and reducing its interaction with proteins involved in ubiquitin-degradation pathway in lung cancer cells (21). Interestingly, HNRNPU is found to be able to stabilize MYC mRNA in U2OS osteosarcoma cell line and hepatocellular carcinoma cells (50,51). To test whether reduced GAS7 expression could potentially stabilize MYCN mRNA, we measured the MYCN mRNA half-life in the control-or GAS7-knockdown Kelly cells after actinomycin D treatment.…”

Section: Downregulation Of Gas7 Promotes Bone Marrow Metastasis Of Hu...mentioning

confidence: 99%

GAS7 Deficiency Promotes Metastasis in MYCN-Driven Neuroblastoma

et al. 2021

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◥One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression.Significance: Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma.See related commentary by Menard, p. 2815

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The splicing regulatory factor hnRNPU is a novel transcriptional target of c‐Myc in hepatocellular carcinoma

Cited by 17 publications

References 42 publications

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

Identification of heterogeneous nuclear ribonucleoprotein as a candidate biomarker for diagnosis and prognosis of hepatocellular carcinoma

GAS7 Deficiency Promotes Metastasis in MYCN-Driven Neuroblastoma

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