The MiR-5694/AF9/Snail Axis Provides Metastatic Advantages and a Therapeutic Target in Basal-like Breast Cancer

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2020 Nov 22

PMID 33221433

Citations 9

Authors

Xin Tian

Hua Yu

Dong Li

Guojiang Jin

Shundong Dai

Pengchao Gong

Cuicui Kong

Xiongjun Wang

Affiliations

Soon will be listed here.

Abstract

Epigenetic deregulation, especially mutagenesis or the abnormal expression of epigenetic regulatory factors (ERFs), plays an important role in malignant tumorigenesis. To screen natural inhibitors of breast cancer metastasis, we adopted small interfering RNAs (siRNAs) to transiently knock down 591 ERF-coding genes in luminal breast cancer MCF-7 cells and found that depletion of AF9 significantly promoted MCF-7 cell invasion and migration. A mouse model of metastasis further confirmed the suppressive role of AF9 in breast cancer metastasis. RNA profiling revealed enrichment of AF9 targets genes in the epithelial-mesenchymal transition (EMT). Mechanistically, tandem mass spectrometry showed that AF9 interacts with Snail, which hampers Snail transcriptional activity in basal-like breast cancer (BLBC) cells. AF9 reconstitutes an activated state on the promoter of Snail, which is a master regulator of EMT, and derepresses genes by recruiting CBP or GCN5. Additionally, microRNA-5694 (miR-5694) targeted and degraded AF9 messenger RNA (mRNA) in BLBC cells, further enhancing cell invasion and migration. Notably, AF9 and miR-5694 expression in BLBC clinical samples correlated inversely. Hence, miR-5694 mediates downregulation of AF9 and provides metastatic advantages in BLBC. Restoring expression of the metastasis suppressor AF9 is a possible therapeutic strategy against metastatic breast cancer.

Citing Articles

MLLT3 Regulates Melanoma Stemness and Progression by Inhibiting HMGB1 Nuclear Entry and MAGEA1 MC Modification.

Li Y, Liu H, Li J, Fu C, Jiang B, Chen B Adv Sci (Weinh). 2024; 12(10):e2408529.

PMID: 39716999 PMC: 11904942. DOI: 10.1002/advs.202408529.

Unveiling the role of GAS41 in cancer progression.

Ji K, Li L, Liu H, Shen Y, Jiang J, Zhang M Cancer Cell Int. 2023; 23(1):245.

PMID: 37853482 PMC: 10583379. DOI: 10.1186/s12935-023-03098-z.

AF9 sustains glycolysis in colorectal cancer via H3K9ac-mediated PCK2 and FBP1 transcription.

He X, Zhong X, Fang Y, Hu Z, Chen Z, Wang Y Clin Transl Med. 2023; 13(8):e1352.

PMID: 37565737 PMC: 10413954. DOI: 10.1002/ctm2.1352.

Hub gene of disulfidptosis-related immune checkpoints in breast cancer.

Wang Y, Deng Y, Xie H, Cao S Med Oncol. 2023; 40(8):222.

PMID: 37402987 DOI: 10.1007/s12032-023-02073-y.

AF9 targets acetyl-modified STAT6 to diminish purine metabolism and accelerate cell apoptosis during metastasis.

Shao J, Shi T, Chen L, Wang X, Yu H, Feng N Cell Death Differ. 2023; 30(7):1695-1709.

PMID: 37308587 PMC: 10307824. DOI: 10.1038/s41418-023-01172-7.

References

Lin Y, Wu Y, Li J, Dong C, Ye X, Chi Y . The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J. 2010; 29(11):1803-16. PMC: 2885925. DOI: 10.1038/emboj.2010.63. View

Nieto M . The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002; 3(3):155-66. DOI: 10.1038/nrm757. View

Brabletz T, Kalluri R, Nieto M, Weinberg R . EMT in cancer. Nat Rev Cancer. 2018; 18(2):128-134. DOI: 10.1038/nrc.2017.118. View

Chen Y, Wang X . miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2019; 48(D1):D127-D131. PMC: 6943051. DOI: 10.1093/nar/gkz757. View

Wang X, Qiao Y, Xiao M, Wang L, Chen J, Lv W . Opposing Roles of Acetylation and Phosphorylation in LIFR-Dependent Self-Renewal Growth Signaling in Mouse Embryonic Stem Cells. Cell Rep. 2017; 18(4):933-946. DOI: 10.1016/j.celrep.2016.12.081. View

Cheng Y, He C, Wang M, Ma X, Mo F, Yang S . Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019; 4:62. PMC: 6915746. DOI: 10.1038/s41392-019-0095-0. View

Mukherjee N, Corcoran D, Nusbaum J, Reid D, Georgiev S, Hafner M . Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol Cell. 2011; 43(3):327-39. PMC: 3220597. DOI: 10.1016/j.molcel.2011.06.007. View

Striano P, Elia M, Castiglia L, Galesi O, Pelligra S, Striano S . A t(4;9)(q34;p22) translocation associated with partial epilepsy, mental retardation, and dysmorphism. Epilepsia. 2005; 46(8):1322-4. DOI: 10.1111/j.1528-1167.2005.64304.x. View

Vinas-Castells R, Beltran M, Valls G, Gomez I, Garcia J, Montserrat-Sentis B . The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. J Biol Chem. 2009; 285(6):3794-3805. PMC: 2823521. DOI: 10.1074/jbc.M109.065995. View

10.

Pradeepa M, Grimes G, Kumar Y, Olley G, Taylor G, Schneider R . Histone H3 globular domain acetylation identifies a new class of enhancers. Nat Genet. 2016; 48(6):681-6. PMC: 4886833. DOI: 10.1038/ng.3550. View

11.

Feinberg A, Koldobskiy M, Gondor A . Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016; 17(5):284-99. PMC: 4888057. DOI: 10.1038/nrg.2016.13. View

12.

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

13.

Wu Y, Evers B, Zhou B . Small C-terminal domain phosphatase enhances snail activity through dephosphorylation. J Biol Chem. 2008; 284(1):640-648. PMC: 2610500. DOI: 10.1074/jbc.M806916200. View

14.

Fidler I, Kripke M . The challenge of targeting metastasis. Cancer Metastasis Rev. 2015; 34(4):635-41. PMC: 4661188. DOI: 10.1007/s10555-015-9586-9. View

15.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

16.

Milioli H, Tishchenko I, Riveros C, Berretta R, Moscato P . Basal-like breast cancer: molecular profiles, clinical features and survival outcomes. BMC Med Genomics. 2017; 10(1):19. PMC: 5370447. DOI: 10.1186/s12920-017-0250-9. View

17.

Buttner N, Johnsen S, Kugler S, Vogel T . Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proc Natl Acad Sci U S A. 2010; 107(15):7042-7. PMC: 2872432. DOI: 10.1073/pnas.0912041107. View

18.

Esteller M . Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007; 16 Spec No 1:R50-9. DOI: 10.1093/hmg/ddm018. View

19.

Nakamura T, Alder H, Gu Y, Prasad R, Canaani O, Kamada N . Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Proc Natl Acad Sci U S A. 1993; 90(10):4631-5. PMC: 46566. DOI: 10.1073/pnas.90.10.4631. View

20.

Collins E, Appert A, Ariza-McNaughton L, Pannell R, Yamada Y, Rabbitts T . Mouse Af9 is a controller of embryo patterning, like Mll, whose human homologue fuses with Af9 after chromosomal translocation in leukemia. Mol Cell Biol. 2002; 22(20):7313-24. PMC: 139815. DOI: 10.1128/MCB.22.20.7313-7324.2002. View