LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner

Holly B. Kramer; Chun-Fui Lai; Hetal Patel; Manikandan Periyasamy; Meng-Lay Lin; Stephan M. Feller; Frances V. Fuller-Pace; David W. Meek; Simak Ali; Laki Buluwela

doi:10.1093/nar/gkv948

LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner

Holly B. Kramer, Chun-Fui Lai, Hetal Patel, Manikandan Periyasamy, Meng-Lay Lin, Stephan M. Feller, Frances V. Fuller-Pace, David W. Meek, Simak Ali (Lead / Corresponding author), Laki Buluwela (Lead / Corresponding author)

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Abstract

Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 in CRC, we undertook global expression profiling following siRNA-mediated LRH-1 knockdown in HCT116 cells, which require LRH-1 for growth and in HT29 cells, in which LRH-1 does not regulate growth. Interestingly, expression of the cell cycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observed in HT29 cells, where p53 is mutated. p53 dependence for the regulation of p21 by LRH-1 was confirmed by p53 knockdown with siRNA, while LRH-1-regulation of p21 was not evident in HCT116 cells where p53 had been deleted. We demonstrate that LRH-1-mediated p21 regulation in HCT116 cells does not involve altered p53 protein or phosphorylation, and we show that LRH-1 inhibits p53 recruitment to the p21 promoter, likely through a mechanism involving chromatin remodelling. Our study suggests an important role for LRH-1 in the growth of CRC cells that retain wild-type p53.

Original language	English
Pages (from-to)	582-594
Number of pages	13
Journal	Nucleic Acids Research
Volume	44
Issue number	2
Early online date	22 Sept 2015
DOIs	https://doi.org/10.1093/nar/gkv948
Publication status	Published - 29 Jan 2016

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© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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Cite this

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title = "LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner",

abstract = "Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 in CRC, we undertook global expression profiling following siRNA-mediated LRH-1 knockdown in HCT116 cells, which require LRH-1 for growth and in HT29 cells, in which LRH-1 does not regulate growth. Interestingly, expression of the cell cycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observed in HT29 cells, where p53 is mutated. p53 dependence for the regulation of p21 by LRH-1 was confirmed by p53 knockdown with siRNA, while LRH-1-regulation of p21 was not evident in HCT116 cells where p53 had been deleted. We demonstrate that LRH-1-mediated p21 regulation in HCT116 cells does not involve altered p53 protein or phosphorylation, and we show that LRH-1 inhibits p53 recruitment to the p21 promoter, likely through a mechanism involving chromatin remodelling. Our study suggests an important role for LRH-1 in the growth of CRC cells that retain wild-type p53.",

author = "Kramer, {Holly B.} and Chun-Fui Lai and Hetal Patel and Manikandan Periyasamy and Meng-Lay Lin and Feller, {Stephan M.} and Fuller-Pace, {Frances V.} and Meek, {David W.} and Simak Ali and Laki Buluwela",

note = "Cancer Research UK [C37/A12011]; Breast Cancer Campaign [2007MayPR17]; Medical Research Council Doctoral Training Program (DTP) award [G1000390 to H.B.K.]. Funding for open access charge: Imperial College London.",

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T1 - LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner

AU - Kramer, Holly B.

AU - Lai, Chun-Fui

AU - Patel, Hetal

AU - Periyasamy, Manikandan

AU - Lin, Meng-Lay

AU - Feller, Stephan M.

AU - Fuller-Pace, Frances V.

AU - Meek, David W.

AU - Ali, Simak

AU - Buluwela, Laki

N1 - Cancer Research UK [C37/A12011]; Breast Cancer Campaign [2007MayPR17]; Medical Research Council Doctoral Training Program (DTP) award [G1000390 to H.B.K.]. Funding for open access charge: Imperial College London.

PY - 2016/1/29

Y1 - 2016/1/29

N2 - Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 in CRC, we undertook global expression profiling following siRNA-mediated LRH-1 knockdown in HCT116 cells, which require LRH-1 for growth and in HT29 cells, in which LRH-1 does not regulate growth. Interestingly, expression of the cell cycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observed in HT29 cells, where p53 is mutated. p53 dependence for the regulation of p21 by LRH-1 was confirmed by p53 knockdown with siRNA, while LRH-1-regulation of p21 was not evident in HCT116 cells where p53 had been deleted. We demonstrate that LRH-1-mediated p21 regulation in HCT116 cells does not involve altered p53 protein or phosphorylation, and we show that LRH-1 inhibits p53 recruitment to the p21 promoter, likely through a mechanism involving chromatin remodelling. Our study suggests an important role for LRH-1 in the growth of CRC cells that retain wild-type p53.

AB - Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 in CRC, we undertook global expression profiling following siRNA-mediated LRH-1 knockdown in HCT116 cells, which require LRH-1 for growth and in HT29 cells, in which LRH-1 does not regulate growth. Interestingly, expression of the cell cycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observed in HT29 cells, where p53 is mutated. p53 dependence for the regulation of p21 by LRH-1 was confirmed by p53 knockdown with siRNA, while LRH-1-regulation of p21 was not evident in HCT116 cells where p53 had been deleted. We demonstrate that LRH-1-mediated p21 regulation in HCT116 cells does not involve altered p53 protein or phosphorylation, and we show that LRH-1 inhibits p53 recruitment to the p21 promoter, likely through a mechanism involving chromatin remodelling. Our study suggests an important role for LRH-1 in the growth of CRC cells that retain wild-type p53.

U2 - 10.1093/nar/gkv948

DO - 10.1093/nar/gkv948

M3 - Article

C2 - 26400164

SN - 0305-1048

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JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 2

ER -

LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner

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