A P21-ZEB1 Complex Inhibits Epithelial-mesenchymal Transition Through the MicroRNA 183-96-182 Cluster

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2013 Nov 27

PMID 24277930

Citations 66

Authors

Xiao Ling Li

Toshifumi Hara

Youngeun Choi

Murugan Subramanian

Princy Francis

Sven Bilke

Robert L Walker

Marbin Pineda

Yuelin Zhu

Yuan Yang

Ji Luo

Lalage M Wakefield

Thomas Brabletz

Ben Ho Park

Sudha Sharma

Dipanjan Chowdhury

Paul S Meltzer

Ashish Lal

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor p21 acts as a cell cycle inhibitor and has also been shown to regulate gene expression by functioning as a transcription corepressor. Here, we identified p21-regulated microRNAs (miRNAs) by sequencing small RNAs from isogenic p21(+/+) and p21(-/-) cells. Three abundant miRNA clusters, miR-200b-200a-429, miR-200c-141, and miR-183-96-182, were downregulated in p21-deficient cells. Consistent with the known function of the miR-200 family and p21 in inhibition of the epithelial-mesenchymal transition (EMT), we observed EMT upon loss of p21 in multiple model systems. To explore a role of the miR-183-96-182 cluster in EMT, we identified its genome-wide targets and found that miR-183 and miR-96 repressed common targets, including SLUG, ZEB1, ITGB1, and KLF4. Reintroduction of miR-200, miR-183, or miR-96 in p21(-/-) cells inhibited EMT, cell migration, and invasion. Conversely, antagonizing miR-200 and miR-183-96-182 cluster miRNAs in p21(+/+) cells increased invasion and elevated the levels of VIM, ZEB1, and SLUG mRNAs. Furthermore, we found that p21 forms a complex with ZEB1 at the miR-183-96-182 cluster promoter to inhibit transcriptional repression of this cluster by ZEB1, suggesting a reciprocal feedback loop.

Citing Articles

Investigating the miRNA-mRNA interactome of human trabecular meshwork cells treated with TGF-β1 provides insights into the pathogenesis of pseudoexfoliation glaucoma.

Roodnat A, Doyle C, Callaghan B, Lester K, Henry M, Sheridan C PLoS One. 2025; 20(1):e0318125.

PMID: 39883689 PMC: 11781692. DOI: 10.1371/journal.pone.0318125.

miR-96-5p expression is sufficient to induce and maintain the senescent cell fate in the absence of stress.

Santiago F, Adige T, Mahmud S, Dong X, Niedernhofer L, Robbins P Proc Natl Acad Sci U S A. 2024; 121(40):e2321182121.

PMID: 39325426 PMC: 11459134. DOI: 10.1073/pnas.2321182121.

A Boolean model explains phenotypic plasticity changes underlying hepatic cancer stem cells emergence.

Hernandez-Magana A, Bensussen A, Martinez-Garcia J, Alvarez-Buylla E NPJ Syst Biol Appl. 2024; 10(1):99.

PMID: 39223160 PMC: 11369243. DOI: 10.1038/s41540-024-00422-9.

MicroRNA Expression Profiles in Human Samples and Cell Lines Revealed Nine miRNAs Associated with Cisplatin Resistance in High-Grade Serous Ovarian Cancer.

Flores-Colon M, Rivera-Serrano M, Reyes-Burgos V, Rolon J, Perez-Santiago J, Marcos-Martinez M Int J Mol Sci. 2024; 25(7).

PMID: 38612604 PMC: 11011404. DOI: 10.3390/ijms25073793.

MicroRNA-183 cluster: a promising biomarker and therapeutic target in gastrointestinal malignancies.

Zheng Y, Sukocheva O, Tse E, Neganova M, Aleksandrova Y, Zhao R Am J Cancer Res. 2024; 13(12):6147-6175.

PMID: 38187051 PMC: 10767355.

References

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C . let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007; 131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054. View

Suzuki H, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K . Modulation of microRNA processing by p53. Nature. 2009; 460(7254):529-33. DOI: 10.1038/nature08199. View

Lowery A, Miller N, Dwyer R, Kerin M . Dysregulated miR-183 inhibits migration in breast cancer cells. BMC Cancer. 2010; 10:502. PMC: 2955037. DOI: 10.1186/1471-2407-10-502. View

Waldman T, Kinzler K, Vogelstein B . p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res. 1995; 55(22):5187-90. View

Fabian M, Sonenberg N . The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nat Struct Mol Biol. 2012; 19(6):586-93. DOI: 10.1038/nsmb.2296. View

Perkins N . Not just a CDK inhibitor: regulation of transcription by p21(WAF1/CIP1/SDI1). Cell Cycle. 2002; 1(1):39-41. View

Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N . Widespread changes in protein synthesis induced by microRNAs. Nature. 2008; 455(7209):58-63. DOI: 10.1038/nature07228. View

Weeraratne S, Amani V, Teider N, Pierre-Francois J, Winter D, Kye M . Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma. Acta Neuropathol. 2012; 123(4):539-52. PMC: 6172007. DOI: 10.1007/s00401-012-0969-5. View

Ferrandiz N, Caraballo J, Garcia-Gutierrez L, Devgan V, Rodriguez-Paredes M, Lafita M . p21 as a transcriptional co-repressor of S-phase and mitotic control genes. PLoS One. 2012; 7(5):e37759. PMC: 3360621. DOI: 10.1371/journal.pone.0037759. View

10.

Korpal M, Ell B, Buffa F, Ibrahim T, Blanco M, Celia-Terrassa T . Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011; 17(9):1101-8. PMC: 3169707. DOI: 10.1038/nm.2401. View

11.

White D, Kurpios N, Zuo D, Hassell J, Blaess S, Mueller U . Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 2004; 6(2):159-70. DOI: 10.1016/j.ccr.2004.06.025. View

12.

Ma L, Teruya-Feldstein J, Weinberg R . Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007; 449(7163):682-8. DOI: 10.1038/nature06174. View

13.

Djuranovic S, Nahvi A, Green R . miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science. 2012; 336(6078):237-40. PMC: 3971879. DOI: 10.1126/science.1215691. View

14.

Liu M, Casimiro M, Wang C, Shirley L, Jiao X, Katiyar S . p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci U S A. 2009; 106(45):19035-9. PMC: 2776463. DOI: 10.1073/pnas.0910009106. View

15.

Cimmino A, Calin G, Fabbri M, Iorio M, Ferracin M, Shimizu M . miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005; 102(39):13944-9. PMC: 1236577. DOI: 10.1073/pnas.0506654102. View

16.

Lim L, Lau N, Garrett-Engele P, Grimson A, Schelter J, Castle J . Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005; 433(7027):769-73. DOI: 10.1038/nature03315. View

17.

Chang B, Watanabe K, Broude E, Fang J, Poole J, Kalinichenko T . Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A. 2000; 97(8):4291-6. PMC: 18232. DOI: 10.1073/pnas.97.8.4291. View

18.

Berezikov E . Evolution of microRNA diversity and regulation in animals. Nat Rev Genet. 2011; 12(12):846-60. DOI: 10.1038/nrg3079. View

19.

Coqueret O, Gascan H . Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1. J Biol Chem. 2000; 275(25):18794-800. DOI: 10.1074/jbc.M001601200. View

20.

Zhu J, Feng Y, Ke Z, Yang Z, Zhou J, Huang X . Down-regulation of miR-183 promotes migration and invasion of osteosarcoma by targeting Ezrin. Am J Pathol. 2012; 180(6):2440-51. DOI: 10.1016/j.ajpath.2012.02.023. View