LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner
File(s)
Published version
Author(s)
Type
Journal Article
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.
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.
Date Issued
2015-09-22
Date Acceptance
2015-09-12
Citation
Nucleic Acids Research, 2015, 44 (2), pp.582-594
ISSN
1362-4962
Publisher
Oxford University Press (OUP)
Start Page
582
End Page
594
Journal / Book Title
Nucleic Acids Research
Volume
44
Issue
2
Copyright Statement
© 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.
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.
License URL
Sponsor
Breast Cancer Now
Cancer Research UK
Grant Number
2011NovPR31
C37/A12011
Subjects
Developmental Biology
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Publication Status
Published