Expression of SATB1 promotes the growth and metastasis of colorectal cancer.

Yi Zhang,Xiuyun Tian,Chen Yang,Bin Dong,Xiaosun Yuan,Wei Xu,Meng Wei,Chunyi Hao,Xiaoya Guan,Hong Ji,Chunxiang Ye,Yuan Sun,Min Zhao,Masaru Katoh

doi:10.1371/journal.pone.0100413

Abstract

Special AT-rich sequence-binding protein-1 (SATB1) has been identified as a genome organizer that reprograms chromatin organization and transcription profiles. SATB1 promotes tumor growth and metastasis in breast cancer and is associated with poor prognosis in several cancer types. The association between SATB1 and colorectal cancer (CRC) has not been studied intensively. Therefore, this study aimed to investigate the effect of SATB1 on CRC growth and metastasis in vitro and in vivo and its correlation with overall survival and clinicopathological factors in CRC patients. Stable SATB1 knockdown and SATB1-overexpressing cell lines were established. SATB1 knockdown decreased cell growth, colony formation, migration, and invasion and increased apoptosis in CRC cells in vitro (p<0.05), whereas SATB1 overexpression had the opposite effect. SATB1 overexpression increased tumor growth and metastasis to lung and liver in vivo by using xenograft animal models (p<0.05). Thus, SATB1 promoted an aggressive CRC phenotype in vitro and in vivo. Immunohistochemical analysis of 560 CRC specimens showed that SATB1 expression was significantly higher in CRC tissues than in matched non-tumor mucosa (p<0.001). In addition, SATB1 expression was significantly higher in patients with poorly differentiated tumors, higher invasion depth, distant metastasis, and advanced TNM stage. SATB1-positive patients had a poorer prognosis than SATB1-negative patients, and SATB1 was identified as an independent prognostic factor for CRC (p = 0.009). Strikingly, we also evaluated SATB2 expression in CRC and found that SATB2 was more abundantly expressed in non-cancerous mucosa compared to colorectal cancer tissues (p<0.001). However, SATB2 expression had no influence on prognosis of CRC patients (p = 0.836). SATB1 expression was significantly associated with shorter survival time either in SATB2-positive patients or in SATB2-negative patients (p<0.001). In conclusion, our findings indicated an important role for SATB1 in CRC tumorigenesis and metastasis. Therefore, SATB1 may represent an important prognostic biomarker and therapeutic target for CRC.

Highlights

Colorectal cancer (CRC) is the third leading cause of cancerassociated death in the United States of America [1] and the second most prevalent cancer in China [2]
We demonstrated the involvement of SATB1 in colorectal cancer (CRC) growth and metastasis based on the following evidence: (a) SATB1 overexpression was detected in both CRC cell lines and CRC tumors, (b) growth and colony formation rates were down regulated in SATB1-knockdown cells but up regulated in SATB1overexpressing cells, (c) migration and invasion capabilities were much poorer in SATB1-knockdown cells, whereas more aggressive in SATB1-overexpressing cells, (d) SATB1 overexpression promoted carcinogenesis and metastasis in vivo by using animal models, (e) the expression of SATB1 protein was more abundant in CRC tissues than in matched non-cancerous tissues, and (f) SATB1 expression was found to be an independent prognostic factor for CRC patients
SATB1 mRNA and protein expression were not detected in SW480, SW620, HT-29, and HCT116 cells

Summary

Introduction

Colorectal cancer (CRC) is the third leading cause of cancerassociated death in the United States of America [1] and the second most prevalent cancer in China [2]. Metastatic liver disease is the major cause of death in CRC patients [4]. Special AT-rich sequence-binding protein-1 (SATB1) is a tissuespecific nuclear protein that is predominantly expressed in thymocytes [5] and was originally recognized for its critical role in proper T-cell development [6,7,8]. SATB1 binds special AT-rich anchor sites circumscribing heterochromatin to form a ‘‘cage-like’’ functional nuclear architecture that serves as a landing platform for chromatin-remodeling factors. The SATB1 network may regulate gene expression by altering the functional organization of DNA sequence [9,10]. SATB1 expression markedly altered the expression of over 1000 breast cancer genes including metastasis-associated genes and tumor suppressor genes to promote growth and metastasis of breast tumor [11]. The association between SATB1 and colorectal cancer (CRC) remains unclear

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