SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

Shruthy Suresh; Deniz Durakoglugil; Xiaorong Zhou; Bokai Zhu; Sarah A Comerford; Chao Xing; Xian-Jin Xie; Brian York; Kathryn A O'Donnell

doi:10.1371/journal.pgen.1006650

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SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

Journal article

Open access

Peer reviewed

SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

Shruthy Suresh, Deniz Durakoglugil, Xiaorong Zhou, Bokai Zhu, Sarah A Comerford, Chao Xing, Xian-Jin Xie, Brian York and Kathryn A O'Donnell

PLoS genetics, Vol.13(3), e1006650

03/2017

DOI: 10.1371/journal.pgen.1006650

PMCID: PMC5362238

PMID: 28273073

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Abstract

Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver.

Mutagenesis

Neoplasm Transplantation

Prostatic Neoplasms - metabolism

Cell Proliferation

Humans

Male

Nuclear Receptor Coactivator 2 - metabolism

Mice, 129 Strain

Carcinogenesis

Immunoglobulins - metabolism

Intercellular Signaling Peptides and Proteins - metabolism

Neoplasm Metastasis

Chromatin Immunoprecipitation

Carcinoma, Hepatocellular - genetics

Gene Deletion

Female

Liver Neoplasms - genetics

Cell Survival

Mice, Inbred C57BL

Antineoplastic Agents - chemistry

Cell Adhesion Molecules - metabolism

Proto-Oncogene Proteins c-myc - metabolism

DNA Transposable Elements

Hep G2 Cells

Mice, Knockout

Animals

Sequence Analysis, RNA

Mice, Nude

Alleles

Liver Neoplasms - metabolism

Mice

Proto-Oncogene Proteins c-myc - genetics

Nuclear Receptor Coactivator 2 - genetics

Carcinoma, Hepatocellular - metabolism

Receptors, Cytoplasmic and Nuclear - metabolism

Details

Title: Subtitle: SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer
Creators: Shruthy Suresh - Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America
Deniz Durakoglugil - Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America
Xiaorong Zhou - Department of Immunology, Nantong University School of Medicine, Nantong, China
Bokai Zhu - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America
Sarah A Comerford - Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, United States of America
Chao Xing - McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, United States of America
Xian-Jin Xie - Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States of America
Brian York - Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
Kathryn A O'Donnell - Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States of America
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.13(3), e1006650
DOI: 10.1371/journal.pgen.1006650
PMID: 28273073
PMCID: PMC5362238
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: United States
Grant note: UL1 TR001105 / NCATS NIH HHS
Language: English
Date published: 03/2017
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917787802771

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