TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1

Abstract Background Transmembrane serine protease 4 (TMPRSS4) is a cell surface–anchored serine protease. Elevated expression of TMPRSS4 correlates with poor prognosis in colorectal cancer, gastric cancer, prostate cancer, non–small cell lung cancer, and other cancers. Previously, we demonstrated th...

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Autores principales:	Yunhee Lee, Junghwa Yoon, Dongjoon Ko, Minyeong Yu, Soojin Lee, Semi Kim
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	TMPRSS4 Stemness SOX2 SLUG TWIST1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/43701df16df547d8b5b5b7e5d397dee7
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spelling	oai:doaj.org-article:43701df16df547d8b5b5b7e5d397dee72021-11-28T12:13:44ZTMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST110.1186/s13046-021-02147-71756-9966https://doaj.org/article/43701df16df547d8b5b5b7e5d397dee72021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02147-7https://doaj.org/toc/1756-9966Abstract Background Transmembrane serine protease 4 (TMPRSS4) is a cell surface–anchored serine protease. Elevated expression of TMPRSS4 correlates with poor prognosis in colorectal cancer, gastric cancer, prostate cancer, non–small cell lung cancer, and other cancers. Previously, we demonstrated that TMPRSS4 promotes invasion and proliferation of prostate cancer cells. Here, we investigated whether TMPRSS4 confers cancer stem–like properties to prostate cancer cells and characterized the underlying mechanisms. Methods Acquisition of cancer stem–like properties by TMPRSS4 was examined by monitoring anchorage-independent growth, tumorsphere formation, aldehyde dehydrogenase (ALDH) activation, and resistance to anoikis and drugs in vitro and in an early metastasis model in vivo. The underlying molecular mechanisms were evaluated, focusing on stemness-related factors regulated by epithelial–mesenchymal transition (EMT)-inducing transcription factors. Clinical expression and significance of TMPRSS4 and stemness-associated factors were explored by analyzing datasets from The Cancer Genome Atlas (TCGA). Results TMPRSS4 promoted anchorage-independent growth, ALDH activation, tumorsphere formation, and therapeutic resistance of prostate cancer cells. In addition, TMPRSS4 promoted resistance to anoikis, thereby increasing survival of circulating tumor cells and promoting early metastasis. These features were accompanied by upregulation of stemness-related factors such as SOX2, BMI1, and CD133. SLUG and TWIST1, master EMT-inducing transcription factors, made essential contributions to TMPRSS4-mediated cancer stem cell (CSC) features through upregulation of SOX2. SLUG stabilized SOX2 via preventing proteasomal degradation through its interaction with SOX2, while TWIST1 upregulated transcription of SOX2 by interacting with the proximal E-box element in the SOX2 promoter. Clinical data showed that TMPRSS4 expression correlated with the levels of SOX2, PROM1, SNAI2, and TWIST1. Expression of SOX2 was positively correlated with that of TWIST1, but not with other EMT-inducing transcription factors, in various cancer cell lines. Conclusions Together, these findings suggest that TMPRSS4 promotes CSC features in prostate cancer through upregulation of the SLUG- and TWIST1-induced stem cell factor SOX2 beyond EMT. Thus, TMPRSS4/SLUG–TWIST1/SOX2 axis may represent a novel mechanism involved in the control of tumor progression.Yunhee LeeJunghwa YoonDongjoon KoMinyeong YuSoojin LeeSemi KimBMCarticleTMPRSS4StemnessSOX2SLUGTWIST1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TMPRSS4 Stemness SOX2 SLUG TWIST1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	TMPRSS4 Stemness SOX2 SLUG TWIST1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yunhee Lee Junghwa Yoon Dongjoon Ko Minyeong Yu Soojin Lee Semi Kim TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1
description	Abstract Background Transmembrane serine protease 4 (TMPRSS4) is a cell surface–anchored serine protease. Elevated expression of TMPRSS4 correlates with poor prognosis in colorectal cancer, gastric cancer, prostate cancer, non–small cell lung cancer, and other cancers. Previously, we demonstrated that TMPRSS4 promotes invasion and proliferation of prostate cancer cells. Here, we investigated whether TMPRSS4 confers cancer stem–like properties to prostate cancer cells and characterized the underlying mechanisms. Methods Acquisition of cancer stem–like properties by TMPRSS4 was examined by monitoring anchorage-independent growth, tumorsphere formation, aldehyde dehydrogenase (ALDH) activation, and resistance to anoikis and drugs in vitro and in an early metastasis model in vivo. The underlying molecular mechanisms were evaluated, focusing on stemness-related factors regulated by epithelial–mesenchymal transition (EMT)-inducing transcription factors. Clinical expression and significance of TMPRSS4 and stemness-associated factors were explored by analyzing datasets from The Cancer Genome Atlas (TCGA). Results TMPRSS4 promoted anchorage-independent growth, ALDH activation, tumorsphere formation, and therapeutic resistance of prostate cancer cells. In addition, TMPRSS4 promoted resistance to anoikis, thereby increasing survival of circulating tumor cells and promoting early metastasis. These features were accompanied by upregulation of stemness-related factors such as SOX2, BMI1, and CD133. SLUG and TWIST1, master EMT-inducing transcription factors, made essential contributions to TMPRSS4-mediated cancer stem cell (CSC) features through upregulation of SOX2. SLUG stabilized SOX2 via preventing proteasomal degradation through its interaction with SOX2, while TWIST1 upregulated transcription of SOX2 by interacting with the proximal E-box element in the SOX2 promoter. Clinical data showed that TMPRSS4 expression correlated with the levels of SOX2, PROM1, SNAI2, and TWIST1. Expression of SOX2 was positively correlated with that of TWIST1, but not with other EMT-inducing transcription factors, in various cancer cell lines. Conclusions Together, these findings suggest that TMPRSS4 promotes CSC features in prostate cancer through upregulation of the SLUG- and TWIST1-induced stem cell factor SOX2 beyond EMT. Thus, TMPRSS4/SLUG–TWIST1/SOX2 axis may represent a novel mechanism involved in the control of tumor progression.
format	article
author	Yunhee Lee Junghwa Yoon Dongjoon Ko Minyeong Yu Soojin Lee Semi Kim
author_facet	Yunhee Lee Junghwa Yoon Dongjoon Ko Minyeong Yu Soojin Lee Semi Kim
author_sort	Yunhee Lee
title	TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1
title_short	TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1
title_full	TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1
title_fullStr	TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1
title_full_unstemmed	TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1
title_sort	tmprss4 promotes cancer stem–like properties in prostate cancer cells through upregulation of sox2 by slug and twist1
publisher	BMC
publishDate	2021
url	https://doaj.org/article/43701df16df547d8b5b5b7e5d397dee7
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TMPRSS4 promotes cancer stem–like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1

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