Essential Role of JunD in Cell Proliferation is Mediated Via MYC Signaling in Prostate Cancer Cells

Overview

Journal Cancer Lett

Specialty Oncology

Date 2019 Feb 15

PMID 30763715

Citations 28

Authors

Bethtrice Elliott

Ana Cecilia Millena

Lilya Matyunina

Mengnan Zhang

Jin Zou

Guangdi Wang

Qiang Zhang

Nathan Bowen

Vanessa Eaton

Gabrielle Webb

Shadyra Thompson

John McDonald

Shafiq Khan

Affiliations

Soon will be listed here.

Abstract

JunD, a member of the AP-1 family, is essential for cell proliferation in prostate cancer (PCa) cells. We recently demonstrated that JunD knock-down (KD) in PCa cells results in cell cycle arrest in G-phase concomitant with a decrease in cyclin D1, Ki67, and c-MYC, but an increase in p21 levels. Furthermore, the over-expression of JunD significantly increased proliferation suggesting JunD regulation of genes required for cell cycle progression. Here, employing gene expression profiling, quantitative proteomics, and validation approaches, we demonstrate that JunD KD is associated with distinct gene and protein expression patterns. Comparative integrative analysis by Ingenuity Pathway Analysis (IPA) identified 1) cell cycle control/regulation as the top canonical pathway whose members exhibited a significant decrease in their expression following JunD KD including PRDX3, PEA15, KIF2C, and CDK2, and 2) JunD dependent genes are associated with cell proliferation, with MYC as the critical downstream regulator. Conversely, JunD over-expression induced the expression of the above genes including c-MYC. We conclude that JunD is a crucial regulator of cell cycle progression and inhibiting its target genes may be an effective approach to block prostate carcinogenesis.

Citing Articles

Genomic clustering tendency of transcription factors reflects phase-separated transcriptional condensates at super-enhancers.

Wang S, Wang Z, Zang C Nucleic Acids Res. 2025; 53(3).

PMID: 39868536 PMC: 11760973. DOI: 10.1093/nar/gkaf015.

Menin in Cancer.

Majer A, Hua X, Katona B Genes (Basel). 2024; 15(9).

PMID: 39336822 PMC: 11431421. DOI: 10.3390/genes15091231.

Single-Nucleus RNA-Seq Characterizes the Cell Types Along the Neuronal Lineage in the Adult Human Subependymal Zone and Reveals Reduced Oligodendrocyte Progenitor Abundance with Age.

Puvogel S, Alsema A, North H, Webster M, Weickert C, Eggen B eNeuro. 2024; 11(3).

PMID: 38351133 PMC: 10913050. DOI: 10.1523/ENEURO.0246-23.2024.

JUND Promotes Tumorigenesis via Specifically Binding on Enhancers of Multiple Oncogenes in Cervical Cancer.

Zhou J, Mo J, Tan C, Xie F, Liang J, Huang W Onco Targets Ther. 2023; 16:347-357.

PMID: 37283647 PMC: 10239735. DOI: 10.2147/OTT.S405027.

Menin-MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers.

Shi Q, Xu M, Kang Z, Zhang M, Luo Y Molecules. 2023; 28(7).

PMID: 37049787 PMC: 10095982. DOI: 10.3390/molecules28073026.

References

Zhou X, Wen Y, Tian Y, He M, Ke X, Huang Z . Heat Shock Protein 90α-Dependent B-Cell-2-Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto-Oncogene c-MYC mRNA Stability. Hepatology. 2018; 69(4):1564-1581. PMC: 6586158. DOI: 10.1002/hep.30172. View

Prensner J, Chen W, Han S, Iyer M, Cao Q, Kothari V . The long non-coding RNA PCAT-1 promotes prostate cancer cell proliferation through cMyc. Neoplasia. 2014; 16(11):900-8. PMC: 4240923. DOI: 10.1016/j.neo.2014.09.001. View

Vo B, Khan S . Expression of nodal and nodal receptors in prostate stem cells and prostate cancer cells: autocrine effects on cell proliferation and migration. Prostate. 2011; 71(10):1084-96. PMC: 3139718. DOI: 10.1002/pros.21326. View

Williams K, Fernandez S, Stien X, Ishii K, Love H, Lau Y . Unopposed c-MYC expression in benign prostatic epithelium causes a cancer phenotype. Prostate. 2005; 63(4):369-84. DOI: 10.1002/pros.20200. View

Mateyak M, Obaya A, Sedivy J . c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol. 1999; 19(7):4672-83. PMC: 84265. DOI: 10.1128/MCB.19.7.4672. View

Zerbini L, de Vasconcellos J, Czibere A, Wang Y, Paccez J, Gu X . JunD-mediated repression of GADD45α and γ regulates escape from cell death in prostate cancer. Cell Cycle. 2011; 10(15):2583-91. PMC: 3180197. DOI: 10.4161/cc.10.15.16057. View

Montironi R, Mazzucchelli R, Lopez-Beltran A, Scarpelli M, Cheng L . Prostatic intraepithelial neoplasia: its morphological and molecular diagnosis and clinical significance. BJU Int. 2011; 108(9):1394-401. DOI: 10.1111/j.1464-410X.2011.010413.x. View

Tian T, Wang M, Zhu Y, Zhu W, Yang T, Li H . Expression, Clinical Significance, and Functional Prediction of MNX1 in Breast Cancer. Mol Ther Nucleic Acids. 2018; 13:399-406. PMC: 6205149. DOI: 10.1016/j.omtn.2018.09.014. View

Chandran U, Ma C, Dhir R, Bisceglia M, Lyons-Weiler M, Liang W . Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer. 2007; 7:64. PMC: 1865555. DOI: 10.1186/1471-2407-7-64. View

10.

Rodriguez-Bravo V, Carceles-Cordon M, Hoshida Y, Cordon-Cardo C, Galsky M, Domingo-Domenech J . The role of GATA2 in lethal prostate cancer aggressiveness. Nat Rev Urol. 2016; 14(1):38-48. PMC: 5489122. DOI: 10.1038/nrurol.2016.225. View

11.

Delmore J, Issa G, Lemieux M, Rahl P, Shi J, Jacobs H . BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146(6):904-17. PMC: 3187920. DOI: 10.1016/j.cell.2011.08.017. View

12.

Katabami M, Donninger H, Hommura F, Leaner V, Kinoshita I, Chick J . Cyclin A is a c-Jun target gene and is necessary for c-Jun-induced anchorage-independent growth in RAT1a cells. J Biol Chem. 2005; 280(17):16728-38. DOI: 10.1074/jbc.M413892200. View

13.

Mao X, Orchard G . Abnormal AP-1 protein expression in primary cutaneous B-cell lymphomas. Br J Dermatol. 2008; 159(1):145-51. DOI: 10.1111/j.1365-2133.2008.08579.x. View

14.

Vartanian R, Masri J, Martin J, Cloninger C, Holmes B, Artinian N . AP-1 regulates cyclin D1 and c-MYC transcription in an AKT-dependent manner in response to mTOR inhibition: role of AIP4/Itch-mediated JUNB degradation. Mol Cancer Res. 2010; 9(1):115-30. PMC: 3105464. DOI: 10.1158/1541-7786.MCR-10-0105. View

15.

Caggia S, Chunduri H, Millena A, Perkins J, Venugopal S, Vo B . Novel role of Giα2 in cell migration: Downstream of PI3-kinase-AKT and Rac1 in prostate cancer cells. J Cell Physiol. 2018; 234(1):802-815. PMC: 6202161. DOI: 10.1002/jcp.26894. View

16.

Rebello R, Pearson R, Hannan R, Furic L . Therapeutic Approaches Targeting MYC-Driven Prostate Cancer. Genes (Basel). 2017; 8(2). PMC: 5333060. DOI: 10.3390/genes8020071. View

17.

Kharman-Biz A, Gao H, Ghiasvand R, Zhao C, Zendehdel K, Dahlman-Wright K . Expression of activator protein-1 (AP-1) family members in breast cancer. BMC Cancer. 2013; 13:441. PMC: 3849565. DOI: 10.1186/1471-2407-13-441. View

18.

Scully K, Lahmy R, Signaevskaia L, Sasik R, Medal R, Kim H . E47 Governs the MYC-CDKN1B/p27-RB Network to Growth Arrest PDA Cells Independent of CDKN2A/p16 and Wild-Type p53. Cell Mol Gastroenterol Hepatol. 2018; 6(2):181-198. PMC: 6039985. DOI: 10.1016/j.jcmgh.2018.05.002. View

19.

Burton L, Rivera M, Hawsawi O, Zou J, Hudson T, Wang G . Muscadine Grape Skin Extract Induces an Unfolded Protein Response-Mediated Autophagy in Prostate Cancer Cells: A TMT-Based Quantitative Proteomic Analysis. PLoS One. 2016; 11(10):e0164115. PMC: 5068743. DOI: 10.1371/journal.pone.0164115. View

20.

Wang Z, Yang B, Zhang M, Guo W, Wu Z, Wang Y . lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer. Cancer Cell. 2018; 33(4):706-720.e9. PMC: 6143179. DOI: 10.1016/j.ccell.2018.03.006. View