Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

Yu,Fang; Jin,Liang; Yang,Guodong; Ji,Lin; Wang,Feng; Lu,Zifan

doi:10.3892/or.2013.2957

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

Authors:
- Fang Yu
- Liang Jin
- Guodong Yang
- Lin Ji
- Feng Wang
- Zifan Lu
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Affiliations: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, P.R. China, Department of Toxicology, The Fourth Military Medical University, Xi'an 710032, P.R. China, Department of Nutrition and Food Hygiene, The Fourth Military Medical University, Xi'an 710032, P.R. China
Published online on: December 31, 2013 https://doi.org/10.3892/or.2013.2957
Pages: 1459-1465

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Abstract

The RNA-binding protein Quaking (QKI) is known to be essential for embryonic development and postnatal myelination. Forkhead box O1 (FOXO1) is a critical tumor suppressor for cell proliferation control. Dysregulation of FOXO1 expression has been observed in a variety of cancers. In the present study, we demonstrated that QKI decreased FOXO1 mRNA expression at the post-transcriptional level. QKI was able to bind the 3'UTR of FOXO1 mRNA directly and decreased its mRNA stability. To determine whether QKI-mediated post-transcriptional repression of FOXO1 indeed plays a role in cancer cells, we first detected both QKI and FOXO1 expression in four breast cancer cell lines. FOXO1 expression was extremely low in these cell lines, whereas QKI expression was relative high. Knockdown of QKI significantly restored FOXO1 expression. ATRA, an inducer of apoptosis or differentiation, dramatically enhanced FOXO1 expression while it repressed QKI expression. Importantly, the ATRA-induced increase in FOXO1 expression was dependent on QKI-mediated post-transcriptional regulation. Consistently, 5-FU, a widely used chemotherapeutic agent, increased FOXO1 expression via inhibition of QKI. In summary, our study provides initial evidence demonstrating that QKI-mediated repression of FOXO1 may be one of the factors contributing to the oncogenesis and progression of breast carcinoma, which suggests that targeting QKI may serve as a novel strategy to sensitize breast cancers to chemotherapy.

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1	Sidman RL, Dickie MM and Appel SH: Mutant mice (Quaking and Jimpy) with deficient myelination in the central nervous system. Science. 144:309–311. 1964. View Article : Google Scholar : PubMed/NCBI
2	Ebersole T, Rho O and Artzt K: The proximal end of mouse chromosome 17: new molecular markers identify a deletion associated with quakingviable. Genetics. 131:183–190. 1992.PubMed/NCBI
3	Kondo T, Furuta T, Mitsunaga K, et al: Genomic organization and expression analysis of the mouse qkI locus. Mamm Genome. 10:662–669. 1999.PubMed/NCBI
4	Pilotte J, Larocque D and Richard S: Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer. Genes Dev. 15:845–858. 2001. View Article : Google Scholar : PubMed/NCBI
5	McInnes LA and Lauriat TL: RNA metabolism and dysmyelination in schizophrenia. Neurosci Biobehav Rev. 30:551–561. 2006. View Article : Google Scholar : PubMed/NCBI
6	Larocque D, Pilotte J, Chen T, et al: Nuclear retention of MBP mRNAs in the quaking viable mice. Neuron. 36:815–829. 2002. View Article : Google Scholar : PubMed/NCBI
7	Zhang Y and Feng Y: Distinct molecular mechanisms lead to diminished myelin basic protein and 2′,3′-cyclic nucleotide 3′-phosphodiesterase in qk(v) dysmyelination. J Neurochem. 77:165–172. 2001.PubMed/NCBI
8	Zhao L, Mandler MD, Yi H and Feng Y: Quaking I controls a unique cytoplasmic pathway that regulates alternative splicing of myelin-associated glycoprotein. Proc Natl Acad Sci USA. 107:19061–19066. 2010. View Article : Google Scholar : PubMed/NCBI
9	van der Veer EP, de Bruin RG, Kraaijeveld AO, et al: The RNA-binding protein quaking is a critical regulator of vascular smooth muscle cell phenotype. Circ Res. 113:1065–1075. 2013.PubMed/NCBI
10	Li Z, Zhang Y, Li D and Feng Y: Destabilization and mislocalization of myelin basic protein mRNAs in quaking dysmyelination lacking the QKI RNA-binding proteins. J Neurosci. 20:4944–4953. 2000.PubMed/NCBI
11	Rosenbluth J and Bobrowski-Khoury N: Structural bases for central nervous system malfunction in the quaking mouse: dysmyelination in a potential model of schizophrenia. J Neurosci Res. 91:374–381. 2013. View Article : Google Scholar : PubMed/NCBI
12	Chubb C: Oligotriche and quaking gene mutations. Phenotypic effects on mouse spermatogenesis and testicular steroidogenesis. J Androl. 13:312–317. 1992.PubMed/NCBI
13	Hall MP, Nagel RJ, Fagg WS, et al: Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation. RNA. 19:627–638. 2013. View Article : Google Scholar : PubMed/NCBI
14	Guo W, Shi X, Liu A, et al: RNA binding protein QKI inhibits the ischemia/reperfusion-induced apoptosis in neonatal cardiomyocytes. Cell Physiol Biochem. 28:593–602. 2011. View Article : Google Scholar : PubMed/NCBI
15	Fu H, Yang G, Wei M, et al: The RNA-binding protein QKI5 is a direct target of C/EBPalpha and delays macrophage differentiation. Mol Biol Cell. 23:1628–1635. 2012. View Article : Google Scholar : PubMed/NCBI
16	Galarneau A and Richard S: Target RNA motif and target mRNAs of the Quaking STAR protein. Nat Struct Mol Biol. 12:691–698. 2005. View Article : Google Scholar : PubMed/NCBI
17	Diep CH, Charles NJ, Gilks CB, Kalloger SE, Argenta PA and Lange CA: Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells. Cell Cycle. 12:1433–1449. 2013. View Article : Google Scholar : PubMed/NCBI
18	Coffer PJ and Burgering BM: Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol. 4:889–899. 2004. View Article : Google Scholar : PubMed/NCBI
19	Paik JH, Kollipara R, Chu G, et al: FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 128:309–323. 2007. View Article : Google Scholar : PubMed/NCBI
20	Pohl BS, Schön C, Rössner A and Knöchel W: The FoxO-subclass in Xenopus laevis development. Gene Expr Patterns. 5:187–192. 2004. View Article : Google Scholar : PubMed/NCBI
21	Lee SY, Lee GR, Woo DH, et al: Depletion of Aurora A leads to upregulation of FoxO1 to induce cell cycle arrest in hepatocellular carcinoma cells. Cell Cycle. 12:67–75. 2013. View Article : Google Scholar : PubMed/NCBI
22	Zhang X, Yalcin S, Lee DF, et al: FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol. 13:1092–1099. 2011. View Article : Google Scholar : PubMed/NCBI
23	Zhang X, Tang N, Hadden TJ and Rishi AK: Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 1813:1978–1986. 2011. View Article : Google Scholar : PubMed/NCBI
24	Guttilla IK and White BA: Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J Biol Chem. 284:23204–23216. 2009. View Article : Google Scholar : PubMed/NCBI
25	Li J, Yang L, Song L, et al: Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1. Oncogene. 28:3188–3196. 2009. View Article : Google Scholar : PubMed/NCBI
26	Silva J, Cavazos DA, Donzis E, Friedrichs WE, Marciniak R and deGraffenried LA: Akt-induced tamoxifen resistance is associated with altered FKHR regulation. Cancer Invest. 25:569–573. 2007. View Article : Google Scholar : PubMed/NCBI
27	Arden KC: Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer. Exp Gerontol. 41:709–717. 2006. View Article : Google Scholar : PubMed/NCBI
28	Wu Z, Sun H, Zeng W, He J and Mao X: Upregulation of MircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1. PLoS One. 7:e458252012. View Article : Google Scholar : PubMed/NCBI
29	Guo Y, Liu H, Zhang H, Shang C and Song Y: miR-96 regulates FOXO1-mediated cell apoptosis in bladder cancer. Oncol Lett. 4:561–565. 2012.PubMed/NCBI
30	Lotan R: Retinoids in cancer chemoprevention. FASEB J. 10:1031–1039. 1996.PubMed/NCBI
31	Yang QJ, Zhou LY, Mu YQ, et al: All-trans retinoic acid inhibits tumor growth of human osteosarcoma by activating Smad signaling-induced osteogenic differentiation. Int J Oncol. 41:153–160. 2012.
32	Chen S, Fang Y, Ma L, Liu S and Li X: Realgar-induced apoptosis and differentiation in all-trans retinoic acid (ATRA)-sensitive NB4 and ATRA-resistant MR2 cells. Int J Oncol. 40:1089–1096. 2012.PubMed/NCBI
33	Lainey E, Wolfromm A, Sukkurwala AQ, et al: EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D 3 in acute myeloid leukemia cells. Cell Cycle. 12:2978–2991. 2013. View Article : Google Scholar
34	Bengtsson AM, Jonsson G, Magnusson C, Salim T, Axelsson C and Sjolander A: The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells. BMC Cancer. 13:3362013. View Article : Google Scholar : PubMed/NCBI
35	Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA and Weigel RJ: Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family. J Biol Chem. 276:33554–33560. 2001. View Article : Google Scholar : PubMed/NCBI
36	Han CY, Cho KB, Choi HS, Han HK and Kang KW: Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells. Carcinogenesis. 29:1837–1844. 2008. View Article : Google Scholar : PubMed/NCBI
37	Tzivion G and Hay N: PI3K-AKT-FoxO axis in cancer and aging. Biochim Biophys Acta. 1813:19252011. View Article : Google Scholar : PubMed/NCBI
38	Saccomanno L, Loushin C, Jan E, Punkay E, Artzt K and Goodwin EB: The STAR protein QKI-6 is a translational repressor. Proc Natl Acad Sci USA. 96:12605–12610. 1999. View Article : Google Scholar : PubMed/NCBI
39	Schumacher B, Hanazawa M, Lee MH, et al: Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis. Cell. 120:357–368. 2005.PubMed/NCBI
40	Kim DH, Kim JM, Lee EK, et al: Modulation of FoxO1 phosphorylation/acetylation by baicalin during aging. J Nutr Biochem. 23:1277–1284. 2012. View Article : Google Scholar : PubMed/NCBI
41	Birkenkamp KU and Coffer PJ: Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. Biochem Soc Trans. 31:292–297. 2003. View Article : Google Scholar : PubMed/NCBI
42	Finlay D, Patel S, Dickson LM, et al: Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element. BMC Mol Biol. 5:152004. View Article : Google Scholar : PubMed/NCBI
43	Wang W, Yan C, Zhang J, et al: SIRT1 inhibits TNF-alpha-induced apoptosis of vascular adventitial fibroblasts partly through the deacetylation of FoxO1. Apoptosis. 18:689–701. 2013. View Article : Google Scholar : PubMed/NCBI
44	Liu P, Kao TP and Huang H: CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene. 27:4733–4744. 2008. View Article : Google Scholar : PubMed/NCBI
45	Yang G, Fu H, Zhang J, et al: RNA-binding protein quaking, a critical regulator of colon epithelial differentiation and a suppressor of colon cancer. Gastroenterology. 138:231–240.e1–5. 2010. View Article : Google Scholar : PubMed/NCBI
46	Bian Y, Wang L, Lu H, et al: Downregulation of tumor suppressor QKI in gastric cancer and its implication in cancer prognosis. Biochem Biophys Res Commun. 422:187–193. 2012. View Article : Google Scholar : PubMed/NCBI