• ISSN 1674-8301
  • CN 32-1810/R
Volume 35 Issue 5
Sep.  2021
Turn off MathJax
Article Contents
Li Xin, Yang Jian, Chen Xia, Cao Dandan, Xu Eugene Yujun. PUM1 represses CDKN1B translation and contributes to prostate cancer progression[J]. The Journal of Biomedical Research, 2021, 35(5): 371-382. doi: 10.7555/JBR.35.20210067
Citation: Li Xin, Yang Jian, Chen Xia, Cao Dandan, Xu Eugene Yujun. PUM1 represses CDKN1B translation and contributes to prostate cancer progression[J]. The Journal of Biomedical Research, 2021, 35(5): 371-382. doi: 10.7555/JBR.35.20210067

PUM1 represses CDKN1B translation and contributes to prostate cancer progression

doi: 10.7555/JBR.35.20210067
More Information
  • Corresponding author: Eugene Yujun Xu, Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. E-mail: e-xu@northwestern.edu
  • Received: 2021-04-15
  • Revised: 2021-05-20
  • Accepted: 2021-05-25
  • Published: 2021-07-16
  • Issue Date: 2021-09-27
  • Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis; identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics. Highly conserved RNA-binding protein Pumilio-1 (PUM1) regulates mouse growth and cell proliferation, propelling us to examine its role in cancer. We found human PUM1 is highly expressed in a diverse group of cancer, including prostate cancer; enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients. Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels. Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation, and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size. Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B (CDKN1B) protein expression through increased translation but did not impact its mRNA level, while overexpression of PUM1 reduced CDKN1B protein level. Our finding established a critical role of PUM1 mediated translational control, particularly the PUM1-CDKN1B axis, in prostate cancer cell growth and tumorigenesis. We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development.

     

  • loading
  • [1]
    Wurth L, Gebauer F. RNA–binding proteins, multifaceted translational regulators in cancer[J]. Biochim Biophys Acta-Gene Regul Mech, 2015, 1849(7): 881–886. doi: 10.1016/j.bbagrm.2014.10.001
    [2]
    Abdelmohsen K, Gorospe M. Posttranscriptional regulation of cancer traits by HuR[J]. Wileys RNA, 2010, 1(2): 214–229. doi: 10.1002/wrna.4
    [3]
    Vellky JE, McSweeney ST, Ricke EA, et al. RNA–binding protein DDX3 mediates posttranscriptional regulation of androgen receptor: a mechanism of castration resistance[J]. Proc Natl Acad Sci U S A, 2020, 117(45): 28092–28101. doi: 10.1073/pnas.2008479117
    [4]
    Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer[J]. Cell, 2017, 168(4): 629–643. doi: 10.1016/j.cell.2016.12.013
    [5]
    Goldstrohm AC, Hall TMT, McKenney KM. Post–transcriptional regulatory functions of mammalian pumilio proteins[J]. Trends Genet, 2018, 34(12): 972–990. doi: 10.1016/j.tig.2018.09.006
    [6]
    Wickens M, Bernstein DS, Kimble J, et al. A PUF family portrait: 3′ UTR regulation as a way of life[J]. Trends Genet, 2002, 18(3): 150–157. doi: 10.1016/S0168-9525(01)02616-6
    [7]
    Zamore PD, Williamson JR, Lehmann R. The Pumilio protein binds RNA through a conserved domain that defines a new class of RNA–binding proteins[J]. RNA, 1997, 3(12): 1421–1433. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1369583/
    [8]
    Chen D, Zheng W, Lin AP, et al. Pumilio 1 suppresses multiple activators of p53 to safeguard spermatogenesis[J]. Curr Biol, 2012, 22(5): 420–425. doi: 10.1016/j.cub.2012.01.039
    [9]
    Gennarino VA, Singh RK, White JJ, et al. Pumilio1 haploinsufficiency leads to SCA1–like neurodegeneration by increasing wild–type Ataxin1 levels[J]. Cell, 2015, 160(6): 1087–1098. doi: 10.1016/j.cell.2015.02.012
    [10]
    Mak W, Fang C, Holden T, et al. An important role of pumilio 1 in regulating the development of the mammalian female germline[J]. Biol Reprod, 2016, 94(6): 1–11. doi: 10.1095/biolreprod.115.137497
    [11]
    Xu EY, Chang R, Salmon NA, et al. A gene trap mutation of a murine homolog of the Drosophila stem cell factor Pumilio results in smaller testes but does not affect litter size or fertility[J]. Mol Reprod Dev, 2007, 74(7): 912–921. doi: 10.1002/mrd.20687
    [12]
    Zhang M, Chen D, Xia J, et al. Post–transcriptional regulation of mouse neurogenesis by Pumilio proteins[J]. Genes Dev, 2017, 31(13): 1354–1369. doi: 10.1101/gad.298752.117
    [13]
    Lin K, Zhang S, Chen J, et al. Generation and functional characterization of a conditional Pumilio2 null allele[J]. J Biomed Res, 2017, 32(6): 434–441. doi: 10.7555/JBR.32.20170117
    [14]
    Gennarino VA, Palmer EE, McDonell LM, et al. A mild PUM1 mutation is associated with adult–onset ataxia, whereas haploinsufficiency causes developmental delay and seizures[J]. Cell, 2018, 172(5): 924–936. doi: 10.1016/j.cell.2018.02.006
    [15]
    Lin K, Qiang W, Zhu M, et al. Mammalian Pum1 and Pum2 control body size via translational regulation of the cell cycle inhibitor Cdkn1b[J]. Cell Rep, 2019, 26(9): 2434–2450. doi: 10.1016/j.celrep.2019.01.111
    [16]
    Lin K, Zhang S, Shi Q, et al. Essential requirement of mammalian Pumilio family in embryonic development[J]. Mol Biol Cell, 2018, 29(24): 2911–2968. doi: 10.1091/mbc.E18-10-0673
    [17]
    Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy[J]. Nat Rev Cancer, 2008, 8(4): 253–267. doi: 10.1038/nrc2347
    [18]
    Kuczyk M, Machtens S, Hradil K, et al. Predictive value of decreased p27Kip1 protein expression for the recurrence–free and long–term survival of prostate cancer patients[J]. Br J Cancer, 1999, 81(6): 1052–1058. doi: 10.1038/sj.bjc.6690806
    [19]
    Polyak K. The p27Kip1 tumor suppressor gene: still a suspect or proven guilty?[J]. Cancer Cell, 2006, 10(5): 352–354. doi: 10.1016/j.ccr.2006.10.015
    [20]
    Miles WO, Lembo A, Volorio A, et al. Alternative polyadenylation in triple–negative breast tumors allows NRAS and c–JUN to bypass PUMILIO posttranscriptional regulation[J]. Cancer Res, 2016, 76(24): 7231–7241. doi: 10.1158/0008-5472.CAN-16-0844
    [21]
    Miles WO, Tschöp K, Herr A, et al. Pumilio facilitates miRNA regulation of the E2F3 oncogene[J]. Genes Dev, 2012, 26(4): 356–368. doi: 10.1101/gad.182568.111
    [22]
    Naudin C, Hattabi A, Michelet F, et al. PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells[J]. Blood, 2017, 129(18): 2493–2506. doi: 10.1182/blood-2016-10-747436
    [23]
    Uhlen M, Zhang C, Lee S, et al. A pathology atlas of the human cancer transcriptome[J]. Science, 2017, 357(6352): eaan2507. doi: 10.1126/science.aan2507
    [24]
    AACR Project GENIE Consortium. AACR project GENIE: powering precision medicine through an international consortium[J]. Cancer Discov, 2017, 7(8): 818–831. doi: 10.1158/2159-8290.CD-17-0151
    [25]
    De Marzo AM, Meeker AK, Epstein JI, et al. Prostate stem cell compartments: expression of the cell cycle inhibitor p27Kip1 in normal, hyperplastic, and neoplastic cells[J]. Am J Pathol, 1998, 153(3): 911–919. doi: 10.1016/S0002-9440(10)65632-5
    [26]
    Koff A. How to decrease p27Kip1 levels during tumor development[J]. Cancer Cell, 2006, 9(2): 75–76. doi: 10.1016/j.ccr.2006.01.020
    [27]
    Bencivenga D, Caldarelli I, Stampone E, et al. p27Kip1 and human cancers: a reappraisal of a still enigmatic protein[J]. Cancer Lett, 2017, 403: 354–365. doi: 10.1016/j.canlet.2017.06.031
    [28]
    Bochis OV, Irimie A, Pichler M, et al. , Irimie, A., Pichler M, et al. (2015). The Role of Skp2 and its Substrate CDKN1B (p27) in Colorectal Cancer[J]. J Gastrointestin Liver Dis, 2015, 24(2): 225–34. doi: 10.15403/jgld.2014.1121.242.skp2
    [29]
    Kim C, Jeong DE, Heo S, et al. Reduced expression of the RNA–binding protein HuD in pancreatic neuroendocrine tumors correlates with low p27Kip1 levels and poor prognosis[J]. J Pathol, 2018, 246(2): 231–243. doi: 10.1002/path.5135
    [30]
    Lee S, Kopp F, Chang TC, et al. Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins[J]. Cell, 2016, 164(1-2): 69–80. doi: 10.1016/j.cell.2015.12.017
    [31]
    Tichon A, Gil N, Lubelsky Y, et al. A conserved abundant cytoplasmic long noncoding RNA modulates repression by Pumilio proteins in human cells[J]. Nat Commun, 2016, 7(1): 12209. doi: 10.1038/ncomms12209
    [32]
    Chang BL, Zheng SL, Isaacs SD, et al. A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer[J]. Cancer Res, 2004, 64(6): 1997–1999. doi: 10.1158/0008-5472.CAN-03-2340
    [33]
    DeMarzo AM, Nelson WG, Isaacs WB, et al. Pathological and molecular aspects of prostate cancer[J]. Lancet, 2003, 361(9361): 955–964. doi: 10.1016/S0140-6736(03)12779-1
    [34]
    Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration–resistant neuroendocrine prostate cancer[J]. Nat Med, 2016, 22(3): 298–305. doi: 10.1038/nm.4045
    [35]
    Mayr C, Bartel DP. Widespread shortening of 3′ UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells[J]. Cell, 2009, 138(4): 673–684. doi: 10.1016/j.cell.2009.06.016
  • JBR-2021-0067-supplementary.pdf
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(6)

    Article Metrics

    Article views (161) PDF downloads(17) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return