HNRNPU Promotes the Progression of Triple-negative Breast Cancer Via RNA Transcription and Alternative Splicing Mechanisms

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Nov 8

PMID 36347834

Authors

Bo-Yue Han

Zhebin Liu

Xin Hu

Hong Ling

Affiliations

Soon will be listed here.

Abstract

Triple-negative breast cancer (TNBC) is a great detriment to women's health due to the lack of effective therapeutic targets. In this study, we employed an integrated genetic screen to identify a pivotal oncogenic factor, heterogeneous nuclear ribonucleoprotein U (HNRNPU), which is required for the progression of TNBC. We elucidated the pro-oncogenic role of HNRNPU, which can induce the proliferation and migration of TNBC cells via its association with DEAD box helicase 5 (DDX5) protein. Elevated levels of the HNRNPU-DDX5 complex prohibited the intron retention of minichromosome maintenance protein 10 (MCM10) pre-mRNA, decreased nonsense-mediated mRNA decay, and activated Wnt/β-catenin signalling; on the other hand, HNRNPU-DDX5 is located in the transcriptional start sites (TSS) of LIM domain only protein 4 (LMO4) and its upregulation promoted the transcription of LMO4, consequently activating PI3K-Akt-mTOR signalling. Our data highlight the synergetic effects of HNRNPU in RNA transcription and splicing in regulating cancer progression and suggest that HNRNPU may act as a potential molecular target in the treatment of TNBC.

Citing Articles

Astrocytic heterogeneous nuclear ribonucleoprotein U is involved in scar formation after spinal cord injury.

Quan L, Uyeda A, Manabe I, Muramatsu R J Neuroinflammation. 2025; 22(1):28.

PMID: 39891176 PMC: 11786496. DOI: 10.1186/s12974-025-03351-4.

Mechanisms of RNA alternative splicing dysregulation in triple-negative breast cancer.

Cao Z, Li Y Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025; 49(7):1143-1154.

PMID: 39788502 PMC: 11495985. DOI: 10.11817/j.issn.1672-7347.2024.240434.

hnRNPU-mediated pathogenic alternative splicing drives gastric cancer progression.

Jin G, Song Y, Fang S, Yan M, Yang Z, Shao Y J Exp Clin Cancer Res. 2025; 44(1):8.

PMID: 39773744 PMC: 11705778. DOI: 10.1186/s13046-024-03264-9.

DAB2IP loss in luminal a breast cancer leads to NF-κB-associated aggressive oncogenic phenotypes.

Mukherjee A, Kakati R, Van Alsten S, Laws T, Ebbs A, Hollern D JCI Insight. 2024; 9(23).

PMID: 39418101 PMC: 11623953. DOI: 10.1172/jci.insight.171705.

Pathogenic gene connections in type 2 diabetes and non-alcoholic fatty liver disease: a bioinformatics analysis and mouse model investigations experiments.

Chen C, Yang K, Zhang Y, Lu M, Zhao X, Wan Z Nutr Diabetes. 2024; 14(1):60.

PMID: 39107295 PMC: 11303809. DOI: 10.1038/s41387-024-00323-0.

References

Shishkin S, Kovalev L, Pashintseva N, Kovaleva M, Lisitskaya K . Heterogeneous Nuclear Ribonucleoproteins Involved in the Functioning of Telomeres in Malignant Cells. Int J Mol Sci. 2019; 20(3). PMC: 6387250. DOI: 10.3390/ijms20030745. View

Xiao R, Tang P, Yang B, Huang J, Zhou Y, Shao C . Nuclear matrix factor hnRNP U/SAF-A exerts a global control of alternative splicing by regulating U2 snRNP maturation. Mol Cell. 2012; 45(5):656-68. PMC: 3299905. DOI: 10.1016/j.molcel.2012.01.009. View

Nyamao R, Wu J, Yu L, Xiao X, Zhang F . Roles of DDX5 in the tumorigenesis, proliferation, differentiation, metastasis and pathway regulation of human malignancies. Biochim Biophys Acta Rev Cancer. 2018; 1871(1):85-98. DOI: 10.1016/j.bbcan.2018.11.003. View

Ozdilek B, Thompson V, Ahmed N, White C, Batey R, Schwartz J . Intrinsically disordered RGG/RG domains mediate degenerate specificity in RNA binding. Nucleic Acids Res. 2017; 45(13):7984-7996. PMC: 5570134. DOI: 10.1093/nar/gkx460. View

Yang W, Wang L . MCM10 facilitates the invaded/migrated potentials of breast cancer cells via Wnt/β-catenin signaling and is positively interlinked with poor prognosis in breast carcinoma. J Biochem Mol Toxicol. 2019; 33(7):e22330. DOI: 10.1002/jbt.22330. View

Messias A, Harnisch C, Ostareck-Lederer A, Sattler M, Ostareck D . The DICE-binding activity of KH domain 3 of hnRNP K is affected by c-Src-mediated tyrosine phosphorylation. J Mol Biol. 2006; 361(3):470-81. DOI: 10.1016/j.jmb.2006.06.025. View

Cerasuolo A, Buonaguro L, Buonaguro F, Tornesello M . The Role of RNA Splicing Factors in Cancer: Regulation of Viral and Human Gene Expression in Human Papillomavirus-Related Cervical Cancer. Front Cell Dev Biol. 2020; 8:474. PMC: 7303290. DOI: 10.3389/fcell.2020.00474. View

Yang Q, Zhao J, Zhang W, Chen D, Wang Y . Aberrant alternative splicing in breast cancer. J Mol Cell Biol. 2019; 11(10):920-929. PMC: 6884705. DOI: 10.1093/jmcb/mjz033. View

Kedzierska H, Piekielko-Witkowska A . Splicing factors of SR and hnRNP families as regulators of apoptosis in cancer. Cancer Lett. 2017; 396:53-65. DOI: 10.1016/j.canlet.2017.03.013. View

10.

Xuan Y, Wang J, Ban L, Lu J, Yi C, Li Z . hnRNPA2/B1 activates cyclooxygenase-2 and promotes tumor growth in human lung cancers. Mol Oncol. 2016; 10(4):610-24. PMC: 5423139. DOI: 10.1016/j.molonc.2015.11.010. View

11.

Zhao X, Reebye V, Hitchen P, Fan J, Jiang H, Saetrom P . Mechanisms involved in the activation of C/EBPα by small activating RNA in hepatocellular carcinoma. Oncogene. 2019; 38(18):3446-3457. DOI: 10.1038/s41388-018-0665-6. View

12.

Dardenne E, Polay Espinoza M, Fattet L, Germann S, Lambert M, Neil H . RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, miRNA, and splicing programs in cell differentiation. Cell Rep. 2014; 7(6):1900-13. DOI: 10.1016/j.celrep.2014.05.010. View

13.

Jiang Y, Ma D, Suo C, Shi J, Xue M, Hu X . Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies. Cancer Cell. 2019; 35(3):428-440.e5. DOI: 10.1016/j.ccell.2019.02.001. View

14.

Kaida D, Schneider-Poetsch T, Yoshida M . Splicing in oncogenesis and tumor suppression. Cancer Sci. 2012; 103(9):1611-6. PMC: 7659361. DOI: 10.1111/j.1349-7006.2012.02356.x. View

15.

Criscitiello C, Azim Jr H, Schouten P, Linn S, Sotiriou C . Understanding the biology of triple-negative breast cancer. Ann Oncol. 2012; 23 Suppl 6:vi13-8. DOI: 10.1093/annonc/mds188. View

16.

Luqmani Y, Mortimer C, Yiangou C, Johnston C, Bansal G, Sinnett D . Expression of 2 variant forms of fibroblast growth factor receptor 1 in human breast. Int J Cancer. 1995; 64(4):274-9. DOI: 10.1002/ijc.2910640411. View

17.

Katsimpoula S, Patrinou-Georgoula M, Makrilia N, Dimakou K, Guialis A, Orfanidou D . Overexpression of hnRNPA2/B1 in bronchoscopic specimens: a potential early detection marker in lung cancer. Anticancer Res. 2009; 29(4):1373-82. View

18.

Carey L, Winer E, Viale G, Cameron D, Gianni L . Triple-negative breast cancer: disease entity or title of convenience?. Nat Rev Clin Oncol. 2010; 7(12):683-92. DOI: 10.1038/nrclinonc.2010.154. View

19.

Bonnal S, Lopez-Oreja I, Valcarcel J . Roles and mechanisms of alternative splicing in cancer - implications for care. Nat Rev Clin Oncol. 2020; 17(8):457-474. DOI: 10.1038/s41571-020-0350-x. View

20.

Visvader J, Venter D, Hahm K, Santamaria M, Sum E, OReilly L . The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer. Proc Natl Acad Sci U S A. 2001; 98(25):14452-7. PMC: 64702. DOI: 10.1073/pnas.251547698. View