MAP3K4/CBP-regulated H2B Acetylation Controls Epithelial-mesenchymal Transition in Trophoblast Stem Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 May 10

PMID 21549327

Citations 69

Authors

Amy N Abell

Nicole Vincent Jordan

WeiChun Huang

Aleix Prat

Alicia A Midland

Nancy L Johnson

Deborah A Granger

Piotr A Mieczkowski

Charles M Perou

Shawn M Gomez

Leping Li

Gary L Johnson

Affiliations

Soon will be listed here.

Abstract

Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation-regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer.

Citing Articles

Exploring MAP3K genes in gastric cancer: biomarkers, tumor microenvironment dynamics, and chemotherapy resistance.

Wei S, Li Y, Zhou J, Xia Y Hereditas. 2025; 162(1):15.

PMID: 39901302 PMC: 11789369. DOI: 10.1186/s41065-025-00364-0.

MAP3K4 signaling regulates HDAC6 and TRAF4 coexpression and stabilization in trophoblast stem cells.

Nelson H, Mullins N, Abell A J Biol Chem. 2024; 301(2):108116.

PMID: 39710325 PMC: 11787431. DOI: 10.1016/j.jbc.2024.108116.

Reinvesting the cellular properties of human amniotic epithelial cells and their therapeutic innovations.

Yang J, Lu Y, Zhao J, Luo Y, Hao W, Zhang W Front Immunol. 2024; 15:1466529.

PMID: 39474414 PMC: 11518714. DOI: 10.3389/fimmu.2024.1466529.

Single-cell profiling of brain pericyte heterogeneity following ischemic stroke unveils distinct pericyte subtype-targeted neural reprogramming potential and its underlying mechanisms.

Loan A, Awaja N, Lui M, Syal C, Sun Y, Sarma S Theranostics. 2024; 14(16):6110-6137.

PMID: 39431007 PMC: 11488099. DOI: 10.7150/thno.97165.

CHHM: a Manually Curated Catalogue of Human Histone Modifications Revealing Hotspot Regions and Unique Distribution Patterns.

Ma W, Ding X, Xu J, Poon T Int J Biol Sci. 2024; 20(10):3760-3772.

PMID: 39113691 PMC: 11302869. DOI: 10.7150/ijbs.95954.

References

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

Wang Z, Zang C, Rosenfeld J, Schones D, Barski A, Cuddapah S . Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008; 40(7):897-903. PMC: 2769248. DOI: 10.1038/ng.154. View

Abell A, Granger D, Johnson N, Vincent-Jordan N, Dibble C, Johnson G . Trophoblast stem cell maintenance by fibroblast growth factor 4 requires MEKK4 activation of Jun N-terminal kinase. Mol Cell Biol. 2009; 29(10):2748-61. PMC: 2682043. DOI: 10.1128/MCB.01391-08. View

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R . Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell. 2005; 123(5):917-29. DOI: 10.1016/j.cell.2005.08.040. View

Prat A, Parker J, Karginova O, Fan C, Livasy C, Herschkowitz J . Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010; 12(5):R68. PMC: 3096954. DOI: 10.1186/bcr2635. View

Lim E, Vaillant F, Wu D, Forrest N, Pal B, Hart A . Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009; 15(8):907-13. DOI: 10.1038/nm.2000. 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

Tanaka S, Kunath T, Hadjantonakis A, Nagy A, Rossant J . Promotion of trophoblast stem cell proliferation by FGF4. Science. 1998; 282(5396):2072-5. DOI: 10.1126/science.282.5396.2072. View

10.

Thiery J, Acloque H, Huang R, Nieto M . Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-90. DOI: 10.1016/j.cell.2009.11.007. View

11.

Rugg-Gunn P, Cox B, Ralston A, Rossant J . Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo. Proc Natl Acad Sci U S A. 2010; 107(24):10783-90. PMC: 2890770. DOI: 10.1073/pnas.0914507107. View

12.

Neve R, Chin K, Fridlyand J, Yeh J, Baehner F, Fevr T . A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006; 10(6):515-27. PMC: 2730521. DOI: 10.1016/j.ccr.2006.10.008. View

13.

Maupin K, Sinha A, Eugster E, Miller J, Ross J, Paulino V . Glycogene expression alterations associated with pancreatic cancer epithelial-mesenchymal transition in complementary model systems. PLoS One. 2010; 5(9):e13002. PMC: 2946336. DOI: 10.1371/journal.pone.0013002. View

14.

Norwitz E, Schust D, Fisher S . Implantation and the survival of early pregnancy. N Engl J Med. 2002; 345(19):1400-8. DOI: 10.1056/NEJMra000763. View

15.

He S, Nakada D, Morrison S . Mechanisms of stem cell self-renewal. Annu Rev Cell Dev Biol. 2009; 25:377-406. DOI: 10.1146/annurev.cellbio.042308.113248. View

16.

Rebel V, Kung A, Tanner E, Yang H, Bronson R, Livingston D . Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc Natl Acad Sci U S A. 2002; 99(23):14789-94. PMC: 137497. DOI: 10.1073/pnas.232568499. View

17.

Cano A, Perez-Moreno M, Rodrigo I, Locascio A, Blanco M, del Barrio M . The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000; 2(2):76-83. DOI: 10.1038/35000025. View

18.

Abell A, Rivera-Perez J, Cuevas B, Uhlik M, Sather S, Johnson N . Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. Mol Cell Biol. 2005; 25(20):8948-59. PMC: 1265780. DOI: 10.1128/MCB.25.20.8948-8959.2005. View

19.

Ray M, Wistow G, Su Y, Meltzer P, Trent J . AIM1, a novel non-lens member of the betagamma-crystallin superfamily, is associated with the control of tumorigenicity in human malignant melanoma. Proc Natl Acad Sci U S A. 1997; 94(7):3229-34. PMC: 20351. DOI: 10.1073/pnas.94.7.3229. View