Serum- and glucocorticoid-induced kinase SGK1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis

Lennard Yw Lee; Connor E Woolley; Thomas Starkey; Sujata Biswas; Tia S Mirshahi; Chiara Bardella; Stefania Segditsas; Shazia Irshad; Ian Tomlinson

doi:10.1158/1078-0432.CCR-18-1033

Serum- and glucocorticoid-induced kinase SGK1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis

Lennard Yw Lee, Connor E Woolley, Thomas Starkey, Sujata Biswas, Tia S Mirshahi, Chiara Bardella, Stefania Segditsas, Shazia Irshad, Ian Tomlinson

Cancer and Genomic Sciences

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Abstract

BACKGROUND AND AIMS: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, since in colorectal cancer (CRC), the degree of differentiation of a tumour is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer (CRC), there is marked downregulation of SGK1 compared to normal tissue.

METHODS: An inducible SGK1 viral overexpression system was utilised to induce re-expression of SGK1 in CRC cell lines. Transcriptomic and phenotypic analyses of these CRC lines was performed and validation in mouse and human cohorts was performed.

RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Re-expression of SGK1 in CRC cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated in part by SGK1-induced PKP3 expression and increased degradation of MYC.

CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit CRC metastasis.

Original language	English
Journal	Clinical Cancer Research
Early online date	15 Oct 2018
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-1033
Publication status	E-pub ahead of print - 15 Oct 2018

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10.1158/1078-0432.CCR-18-1033Licence: None: All rights reserved

Lee_et_al_Serum-and_glucocorticoid-induced_Clinical_Cancer_Research_2018
Checked for eligibility 22/10/2018 This is the Author Accepted Manuscript of an article published in Clinical Cancer Research. The final published version can be found at: DOI: 10.1158/1078-0432.CCR-18-1033 http://clincancerres.aacrjournals.org/content/early/2018/10/13/1078-0432.CCR-18-1033
Accepted author manuscript, 1.64 MBLicence: None: All rights reserved

http://clincancerres.aacrjournals.org/content/early/2018/10/13/1078-0432.CCR-18-1033Licence: None: All rights reserved

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Lee, L. Y., Woolley, C. E., Starkey, T., Biswas, S., Mirshahi, T. S., Bardella, C., Segditsas, S., Irshad, S., & Tomlinson, I. (2018). Serum- and glucocorticoid-induced kinase SGK1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis. Clinical Cancer Research. Advance online publication. https://doi.org/10.1158/1078-0432.CCR-18-1033

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title = "Serum- and glucocorticoid-induced kinase SGK1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis",

abstract = "BACKGROUND AND AIMS: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, since in colorectal cancer (CRC), the degree of differentiation of a tumour is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer (CRC), there is marked downregulation of SGK1 compared to normal tissue.METHODS: An inducible SGK1 viral overexpression system was utilised to induce re-expression of SGK1 in CRC cell lines. Transcriptomic and phenotypic analyses of these CRC lines was performed and validation in mouse and human cohorts was performed.RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Re-expression of SGK1 in CRC cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated in part by SGK1-induced PKP3 expression and increased degradation of MYC.CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit CRC metastasis.",

author = "Lee, {Lennard Yw} and Woolley, {Connor E} and Thomas Starkey and Sujata Biswas and Mirshahi, {Tia S} and Chiara Bardella and Stefania Segditsas and Shazia Irshad and Ian Tomlinson",

note = "Copyright {\textcopyright}2018, American Association for Cancer Research.",

year = "2018",

month = oct,

day = "15",

doi = "10.1158/1078-0432.CCR-18-1033",

language = "English",

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T1 - Serum- and glucocorticoid-induced kinase SGK1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis

AU - Lee, Lennard Yw

AU - Woolley, Connor E

AU - Starkey, Thomas

AU - Biswas, Sujata

AU - Mirshahi, Tia S

AU - Bardella, Chiara

AU - Segditsas, Stefania

AU - Irshad, Shazia

AU - Tomlinson, Ian

PY - 2018/10/15

Y1 - 2018/10/15

N2 - BACKGROUND AND AIMS: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, since in colorectal cancer (CRC), the degree of differentiation of a tumour is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer (CRC), there is marked downregulation of SGK1 compared to normal tissue.METHODS: An inducible SGK1 viral overexpression system was utilised to induce re-expression of SGK1 in CRC cell lines. Transcriptomic and phenotypic analyses of these CRC lines was performed and validation in mouse and human cohorts was performed.RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Re-expression of SGK1 in CRC cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated in part by SGK1-induced PKP3 expression and increased degradation of MYC.CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit CRC metastasis.

AB - BACKGROUND AND AIMS: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, since in colorectal cancer (CRC), the degree of differentiation of a tumour is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer (CRC), there is marked downregulation of SGK1 compared to normal tissue.METHODS: An inducible SGK1 viral overexpression system was utilised to induce re-expression of SGK1 in CRC cell lines. Transcriptomic and phenotypic analyses of these CRC lines was performed and validation in mouse and human cohorts was performed.RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Re-expression of SGK1 in CRC cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated in part by SGK1-induced PKP3 expression and increased degradation of MYC.CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit CRC metastasis.

U2 - 10.1158/1078-0432.CCR-18-1033

DO - 10.1158/1078-0432.CCR-18-1033

M3 - Article

C2 - 30322876

SN - 1078-0432

JO - Clinical Cancer Research

JF - Clinical Cancer Research

ER -

Serum- and glucocorticoid-induced kinase SGK1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis

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