MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM

Research output: Contribution to journalArticle

Takahiro Kodama, Teresa A Marian, Hubert Lee, Michiko Kodama, Jian Li, Michael S Parmacek, Nancy A Jenkins, Neal G Copeland, Zhubo Wei

Myocardin-related transcription factor B (MRTFB) is a candidate tumor-suppressor gene identified in transposon mutagenesis screens of the intestine, liver, and pancreas. Using a combination of cell-based assays, in vivo tumor xenograft assays, and Mrtfb knockout mice, we demonstrate here that MRTFB is a human and mouse colorectal cancer (CRC) tumor suppressor that functions in part by inhibiting cell invasion and migration. To identify possible MRTFB transcriptional targets, we performed whole transcriptome RNA sequencing in MRTFB siRNA knockdown primary human colon cells and identified 15 differentially expressed genes. Among the top candidate tumor-suppressor targets were melanoma cell adhesion molecule (MCAM), a known tumor suppressor, and spindle apparatus coiled-coil protein 1 (SPDL1), which has no confirmed role in cancer. To determine whether these genes play a role in CRC, we knocked down the expression of MCAM and SPDL1 in human CRC cells and showed significantly increased invasion and migration of tumor cells. We also showed that Spdl1 expression is significantly down-regulated in Mrtfb knockout mouse intestine, while lower SPDL1 expression levels are significantly associated with reduced survival in CRC patients. Finally, we show that depletion of MCAM and SPDL1 in human CRC cells significantly increases tumor development in xenograft assays, further confirming their tumor-suppressive roles in CRC. Collectively, our findings demonstrate the tumor-suppressive role of MRTFB in CRC and identify several genes, including 2 tumor suppressors, that act downstream of MRTFB to regulate tumor growth and survival in CRC patients.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
DOIs
StateE-pub ahead of print - Nov 5 2019

PMID: 31690663

Altmetrics

Cite this

Standard

MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM. / Kodama, Takahiro; Marian, Teresa A; Lee, Hubert; Kodama, Michiko; Li, Jian; Parmacek, Michael S; Jenkins, Nancy A; Copeland, Neal G; Wei, Zhubo.

In: Proceedings of the National Academy of Sciences of the United States of America, 05.11.2019.

Research output: Contribution to journalArticle

Harvard

Kodama, T, Marian, TA, Lee, H, Kodama, M, Li, J, Parmacek, MS, Jenkins, NA, Copeland, NG & Wei, Z 2019, 'MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM' Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1910413116

APA

Kodama, T., Marian, T. A., Lee, H., Kodama, M., Li, J., Parmacek, M. S., ... Wei, Z. (2019). MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1910413116

Vancouver

Kodama T, Marian TA, Lee H, Kodama M, Li J, Parmacek MS et al. MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM. Proceedings of the National Academy of Sciences of the United States of America. 2019 Nov 5. https://doi.org/10.1073/pnas.1910413116

Author

Kodama, Takahiro ; Marian, Teresa A ; Lee, Hubert ; Kodama, Michiko ; Li, Jian ; Parmacek, Michael S ; Jenkins, Nancy A ; Copeland, Neal G ; Wei, Zhubo. / MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM. In: Proceedings of the National Academy of Sciences of the United States of America. 2019.

BibTeX

@article{1142a5d79b9343308a7419529040460a,
title = "MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM",
abstract = "Myocardin-related transcription factor B (MRTFB) is a candidate tumor-suppressor gene identified in transposon mutagenesis screens of the intestine, liver, and pancreas. Using a combination of cell-based assays, in vivo tumor xenograft assays, and Mrtfb knockout mice, we demonstrate here that MRTFB is a human and mouse colorectal cancer (CRC) tumor suppressor that functions in part by inhibiting cell invasion and migration. To identify possible MRTFB transcriptional targets, we performed whole transcriptome RNA sequencing in MRTFB siRNA knockdown primary human colon cells and identified 15 differentially expressed genes. Among the top candidate tumor-suppressor targets were melanoma cell adhesion molecule (MCAM), a known tumor suppressor, and spindle apparatus coiled-coil protein 1 (SPDL1), which has no confirmed role in cancer. To determine whether these genes play a role in CRC, we knocked down the expression of MCAM and SPDL1 in human CRC cells and showed significantly increased invasion and migration of tumor cells. We also showed that Spdl1 expression is significantly down-regulated in Mrtfb knockout mouse intestine, while lower SPDL1 expression levels are significantly associated with reduced survival in CRC patients. Finally, we show that depletion of MCAM and SPDL1 in human CRC cells significantly increases tumor development in xenograft assays, further confirming their tumor-suppressive roles in CRC. Collectively, our findings demonstrate the tumor-suppressive role of MRTFB in CRC and identify several genes, including 2 tumor suppressors, that act downstream of MRTFB to regulate tumor growth and survival in CRC patients.",
author = "Takahiro Kodama and Marian, {Teresa A} and Hubert Lee and Michiko Kodama and Jian Li and Parmacek, {Michael S} and Jenkins, {Nancy A} and Copeland, {Neal G} and Zhubo Wei",
year = "2019",
month = "11",
day = "5",
doi = "10.1073/pnas.1910413116",
language = "English (US)",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",

}

RIS

TY - JOUR

T1 - MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM

AU - Kodama, Takahiro

AU - Marian, Teresa A

AU - Lee, Hubert

AU - Kodama, Michiko

AU - Li, Jian

AU - Parmacek, Michael S

AU - Jenkins, Nancy A

AU - Copeland, Neal G

AU - Wei, Zhubo

PY - 2019/11/5

Y1 - 2019/11/5

N2 - Myocardin-related transcription factor B (MRTFB) is a candidate tumor-suppressor gene identified in transposon mutagenesis screens of the intestine, liver, and pancreas. Using a combination of cell-based assays, in vivo tumor xenograft assays, and Mrtfb knockout mice, we demonstrate here that MRTFB is a human and mouse colorectal cancer (CRC) tumor suppressor that functions in part by inhibiting cell invasion and migration. To identify possible MRTFB transcriptional targets, we performed whole transcriptome RNA sequencing in MRTFB siRNA knockdown primary human colon cells and identified 15 differentially expressed genes. Among the top candidate tumor-suppressor targets were melanoma cell adhesion molecule (MCAM), a known tumor suppressor, and spindle apparatus coiled-coil protein 1 (SPDL1), which has no confirmed role in cancer. To determine whether these genes play a role in CRC, we knocked down the expression of MCAM and SPDL1 in human CRC cells and showed significantly increased invasion and migration of tumor cells. We also showed that Spdl1 expression is significantly down-regulated in Mrtfb knockout mouse intestine, while lower SPDL1 expression levels are significantly associated with reduced survival in CRC patients. Finally, we show that depletion of MCAM and SPDL1 in human CRC cells significantly increases tumor development in xenograft assays, further confirming their tumor-suppressive roles in CRC. Collectively, our findings demonstrate the tumor-suppressive role of MRTFB in CRC and identify several genes, including 2 tumor suppressors, that act downstream of MRTFB to regulate tumor growth and survival in CRC patients.

AB - Myocardin-related transcription factor B (MRTFB) is a candidate tumor-suppressor gene identified in transposon mutagenesis screens of the intestine, liver, and pancreas. Using a combination of cell-based assays, in vivo tumor xenograft assays, and Mrtfb knockout mice, we demonstrate here that MRTFB is a human and mouse colorectal cancer (CRC) tumor suppressor that functions in part by inhibiting cell invasion and migration. To identify possible MRTFB transcriptional targets, we performed whole transcriptome RNA sequencing in MRTFB siRNA knockdown primary human colon cells and identified 15 differentially expressed genes. Among the top candidate tumor-suppressor targets were melanoma cell adhesion molecule (MCAM), a known tumor suppressor, and spindle apparatus coiled-coil protein 1 (SPDL1), which has no confirmed role in cancer. To determine whether these genes play a role in CRC, we knocked down the expression of MCAM and SPDL1 in human CRC cells and showed significantly increased invasion and migration of tumor cells. We also showed that Spdl1 expression is significantly down-regulated in Mrtfb knockout mouse intestine, while lower SPDL1 expression levels are significantly associated with reduced survival in CRC patients. Finally, we show that depletion of MCAM and SPDL1 in human CRC cells significantly increases tumor development in xenograft assays, further confirming their tumor-suppressive roles in CRC. Collectively, our findings demonstrate the tumor-suppressive role of MRTFB in CRC and identify several genes, including 2 tumor suppressors, that act downstream of MRTFB to regulate tumor growth and survival in CRC patients.

U2 - 10.1073/pnas.1910413116

DO - 10.1073/pnas.1910413116

M3 - Article

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

ER -

ID: 54620642