Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis

Peng Shao; Qi Liu; Peterson Kariuki Maina; Jiayue Cui; Thomas B Bair; Tiandao Li; Shaikamjad Umesalma; Weizhou Zhang; Hank Heng Qi

doi:10.1093/nar/gkw1093

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Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis

Journal article

Open access

Peer reviewed

Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis

Peng Shao, Qi Liu, Peterson Kariuki Maina, Jiayue Cui, Thomas B Bair, Tiandao Li, Shaikamjad Umesalma, Weizhou Zhang and Hank Heng Qi

Nucleic Acids Research, Vol.45(4), pp.1687-1702

11/28/2016

DOI: 10.1093/nar/gkw1093

PMCID: PMC5389682

PMID: 27899639

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Published (Version of record)Nucleic Acids Research, Volume 45, Issue 4, 28 February 2017, Pages 1687–1702.

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.

Anatomy

Signal Transduction

Cells

Animals

Breast Neoplasms

Cell Line

Tumor

Cell Movement

Cell Proliferation

Cell Transformation

Neoplastic

Disease Models

Animal

Epithelial-Mesenchymal Transition

Female

Gene Expression Regulation

Heterografts

Histone Demethylases

Histones

Humans

Mice

MicroRNAs

Proto-Oncogene Proteins c-myc

Transcription Factors

Transcriptional Activation

Transforming Growth Factor beta

OAfund

Details

Title: Subtitle: Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis
Creators: Peng Shao - University of Iowa
Qi Liu - University of Iowa
Peterson Kariuki Maina - University of Iowa
Jiayue Cui - Jilin University
Thomas B Bair - University of Iowa
Tiandao Li - Washington University in St. Louis
Shaikamjad Umesalma - University of Iowa
Weizhou Zhang - University of Iowa
Hank Heng Qi - University of Iowa
Resource Type: Journal article
Publication Details: Nucleic Acids Research, Vol.45(4), pp.1687-1702
DOI: 10.1093/nar/gkw1093
PMID: 27899639
PMCID: PMC5389682
NLM abbreviation: Nucleic Acids Res.
ISSN: 1362-4962
Publisher: Oxford University Press
Grant note: Funder: 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 ID: P30 CA86862, IRG-77-004-34, 01-224
Language: English
Date published: 11/28/2016
Academic Unit: Anatomy and Cell Biology; Pathology; Iowa Institute of Human Genetics
Record Identifier: 9983557569402771

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