Requirement of the Histone Demethylase LSD1 in Snai1-mediated Transcriptional Repression During Epithelial-mesenchymal Transition

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2010 Jun 22

PMID 20562920

Citations 151

Authors

T Lin

A Ponn

X Hu

B K Law

J Lu

Affiliations

Soon will be listed here.

Abstract

Epithelial-mesenchymal transition (EMT) has pivotal roles during embryonic development and carcinoma progression. Members of the Snai1 family of zinc finger transcription factors are central mediators of EMT and induce EMT in part by directly repressing epithelial markers such as E-cadherin, a gatekeeper of the epithelial phenotype and a suppressor of tumor invasion. However, the molecular mechanism underlying Snai1-mediated transcriptional repression remains incompletely understood. Here we show that Snai1 physically interacts with and recruits the histone demethylase LSD1 (KDM1A) to epithelial gene promoters. LSD1 removes dimethylation of lysine 4 on histone H3 (H3K4m2), a covalent histone modification associated with active chromatin. Importantly, LSD1 is essential for Snai1-mediated transcriptional repression and for maintenance of the silenced state of Snai1 target genes in invasive cancer cells. In the absence of LSD1, Snai1 fails to repress E-cadherin. In cancer cells in which E-cadherin is silenced, depletion of LSD1 results in partial de-repression of epithelial genes and elevated H3K4m2 levels at the E-cadherin promoter. These results underline the critical role of LSD1 in Snai1-dependent transcriptional repression of epithelial markers and suggest that the LSD1 complex could be a potential therapeutic target for prevention of EMT-associated tumor invasion.

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References

Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine G . Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature. 2007; 446(7138):882-7. DOI: 10.1038/nature05671. View

Shi Y, Lan F, Matson C, Mulligan P, Whetstine J, Cole P . Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004; 119(7):941-53. DOI: 10.1016/j.cell.2004.12.012. 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

Thiery J, Sleeman J . Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7(2):131-42. DOI: 10.1038/nrm1835. View

Ao A, Wang H, Kamarajugadda S, Lu J . Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. Proc Natl Acad Sci U S A. 2008; 105(22):7821-6. PMC: 2409389. DOI: 10.1073/pnas.0711677105. View

Bernstein B, Mikkelsen T, Xie X, Kamal M, Huebert D, Cuff J . A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006; 125(2):315-26. DOI: 10.1016/j.cell.2006.02.041. View

De Craene B, Gilbert B, Stove C, Bruyneel E, van Roy F, Berx G . The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res. 2005; 65(14):6237-44. DOI: 10.1158/0008-5472.CAN-04-3545. View

Yang J, Weinberg R . Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008; 14(6):818-29. DOI: 10.1016/j.devcel.2008.05.009. View

Hajra K, Fearon E . The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002; 62(6):1613-8. View

10.

Polyak K, Weinberg R . Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009; 9(4):265-73. DOI: 10.1038/nrc2620. View

11.

Klose R, Zhang Y . Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol. 2007; 8(4):307-18. DOI: 10.1038/nrm2143. View

12.

Hou Z, Peng H, Ayyanathan K, Yan K, Langer E, Longmore G . The LIM protein AJUBA recruits protein arginine methyltransferase 5 to mediate SNAIL-dependent transcriptional repression. Mol Cell Biol. 2008; 28(10):3198-207. PMC: 2423142. DOI: 10.1128/MCB.01435-07. View

13.

Li B, Carey M, Workman J . The role of chromatin during transcription. Cell. 2007; 128(4):707-19. DOI: 10.1016/j.cell.2007.01.015. View

14.

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

15.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J . The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000; 2(2):84-9. DOI: 10.1038/35000034. View

16.

Perl A, Wilgenbus P, Dahl U, Semb H, Christofori G . A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature. 1998; 392(6672):190-3. DOI: 10.1038/32433. View

17.

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

18.

Saleque S, Kim J, Rooke H, Orkin S . Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol Cell. 2007; 27(4):562-72. DOI: 10.1016/j.molcel.2007.06.039. View

19.

Jenuwein T, Allis C . Translating the histone code. Science. 2001; 293(5532):1074-80. DOI: 10.1126/science.1063127. View

20.

Peinado H, Ballestar E, Esteller M, Cano A . Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 2003; 24(1):306-19. PMC: 303344. DOI: 10.1128/MCB.24.1.306-319.2004. View