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ERR? Regulates OTUB1 Expression to Promote Colorectal Cancer Cell Migration.

ABSTRACT: Ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) is overexpressed in many cancers and plays an important role in tumor progression and metastasis. However, the molecular mechanisms underlying OTUB1 overexpression are not clear. In this study, we found that estrogen-related receptor alpha (ERR?, also called NR3B1) binds to OTUB1 promoter and regulates its expression in colorectal cancer. Furthermore, ERR? promoted the migration of CRC cells by inducing vimentin expression via OTUB1. Our data show that OTUB1 is a novel target of ERR? and indicate that ERR?-OTUB1 signaling may play a significant role in CRC metastasis.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC6843886 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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ERRα Regulates OTUB1 Expression to Promote Colorectal Cancer Cell Migration.

Zhou Yi Y Jia Qingzhu Q Meng Xiaoqing X Chen Diangang D Zhu Bo B

Journal of Cancer 20191006 23

Ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) is overexpressed in many cancers and plays an important role in tumor progression and metastasis. However, the molecular mechanisms underlying OTUB1 overexpression are not clear. In this study, we found that estrogen-related receptor alpha (ERRα, also called NR3B1) binds to <i>OTUB1</i> promoter and regulates its expression in colorectal cancer. Furthermore, ERRα promoted the migration of CRC cells by inducing vimentin ...[more]

PMID: 31737118

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Project description:Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.

Dataset Information

ERR? Regulates OTUB1 Expression to Promote Colorectal Cancer Cell Migration.

Publications

ERRα Regulates OTUB1 Expression to Promote Colorectal Cancer Cell Migration.

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