SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer.
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-03-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC5362238?pdf=render |
| _version_ | 1818391262079746048 |
|---|---|
| author | Shruthy Suresh Deniz Durakoglugil Xiaorong Zhou Bokai Zhu Sarah A Comerford Chao Xing Xian-Jin Xie Brian York Kathryn A O'Donnell |
| author_facet | Shruthy Suresh Deniz Durakoglugil Xiaorong Zhou Bokai Zhu Sarah A Comerford Chao Xing Xian-Jin Xie Brian York Kathryn A O'Donnell |
| author_sort | Shruthy Suresh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T05:10:43Z |
| format | Article |
| id | doaj.art-deb99dc4a1ec4049b3b9f8f4e0ad7a25 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-14T05:10:43Z |
| publishDate | 2017-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-deb99dc4a1ec4049b3b9f8f4e0ad7a252022-12-21T23:15:59ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-03-01133e100665010.1371/journal.pgen.1006650SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer.Shruthy SureshDeniz DurakoglugilXiaorong ZhouBokai ZhuSarah A ComerfordChao XingXian-Jin XieBrian YorkKathryn A O'DonnellHepatocellular 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.http://europepmc.org/articles/PMC5362238?pdf=render |
| spellingShingle | Shruthy Suresh Deniz Durakoglugil Xiaorong Zhou Bokai Zhu Sarah A Comerford Chao Xing Xian-Jin Xie Brian York Kathryn A O'Donnell SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. PLoS Genetics |
| title | SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. |
| title_full | SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. |
| title_fullStr | SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. |
| title_full_unstemmed | SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. |
| title_short | SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. |
| title_sort | src 2 mediated coactivation of anti tumorigenic target genes suppresses myc induced liver cancer |
| url | http://europepmc.org/articles/PMC5362238?pdf=render |
| work_keys_str_mv | AT shruthysuresh src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT denizdurakoglugil src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT xiaorongzhou src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT bokaizhu src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT sarahacomerford src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT chaoxing src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT xianjinxie src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT brianyork src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer AT kathrynaodonnell src2mediatedcoactivationofantitumorigenictargetgenessuppressesmycinducedlivercancer |