Document Type

Article

Peer Reviewed

1

Publication Date

11-28-2016

NLM Title Abbreviation

Nucleic Acids Res.

Journal/Book/Conference Title

Nucleic Acids Research

PubMed ID

27899639

DOI of Published Version

10.1093/nar/gkw1093

Start Page

1687

End Page

1702

Abstract

Histone demethylase PHF8 is upregulated and plays oncogenic roles in various cancers; however, the mechanisms underlying its dysregulation and functions in carcinogenesis remain obscure. Here, we report the novel functions of PHF8 in EMT (epithelial to mesenchymal transition) and breast cancer development. Genome-wide gene expression analysis revealed that PHF8 overexpression induces an EMT-like process, including the upregulation of SNAI1 and ZEB1. PHF8 demethylates H3K9me1, H3K9me2 and sustains H3K4me3 to prime the transcriptional activation of SNAI1 by TGF-β signaling. We show that PHF8 is upregulated and positively correlated with MYC at protein levels in breast cancer. MYC post-transcriptionally regulates the expression of PHF8 via the repression of microRNAs. Specifically, miR-22 directly targets and inhibits PHF8 expression, and mediates the regulation of PHF8 by MYC and TGF-β signaling. This novel MYC/microRNAs/PHF8 regulatory axis thus places PHF8 as an important downstream effector of MYC. Indeed, PHF8 contributes to MYC-induced cell proliferation and the expression of EMT-related genes. We also report that PHF8 plays important roles in breast cancer cell migration and tumor growth. These oncogenic functions of PHF8 in breast cancer confer its candidacy as a promising therapeutic target for this disease.

Keywords

Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic, Disease Models, Animal, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Heterografts, Histone Demethylases, Histones, Humans, Mice, MicroRNAs, Proto-Oncogene Proteins c-myc, Signal Transduction, Transcription Factors, Transcriptional Activation, Transforming Growth Factor beta, OAfund

Granting or Sponsoring Agency

Department of Anatomy and Cell Biology, the Carver College of Medicine, the University of Iowa [Lab startup to H.H.Q.]; Carver Trust Young Investigator Award from the Roy J. Carver Charitable Trust [01-224 to H.H.Q]; The National Institutes of Health and CTSA grant UL1RR024979 through ICTS (Institute for Clinical and Translational Science) at the University of Iowa [Pilot grant to H.H.Q]; ACS-IRG seed grant [IRG-77-004-34 to H.H.Q.] from the American Cancer Society, administrated through the Holden Comprehensive Cancer Center at the University of Iowa; Breast Cancer Research Award [to H.H.Q.] by the Holden Comprehensive Cancer Center at the University of Iowa; The National Institutes of Health grant [P30 CA86862] to the Genomics and Flow Cytometry core facilities at the University of Iowa; Libraries and Provost's Open Access Fund at the University of Iowa for the open access charge.

Grant Number

P30 CA86862, IRG-77-004-34, 01-224

Journal Article Version

Version of Record

Published Article/Book Citation

Nucleic Acids Research, Volume 45, Issue 4, 28 February 2017, Pages 1687–1702, https://doi.org/10.1093/nar/gkw1093

Rights

© The Author(s) 2016.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Included in

Cells Commons

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URL

https://ir.uiowa.edu/anatomy_pubs/2