Heat-shock factor 1 both positively and negatively affects cellular clonogenic growth depending on p53 status

Chau Hoang Nguyen, Benjamin James Lang, Ryan Chau Chia Chai, Jessica Louise Vieusseux, Michelle Maria Kouspou, John Timothy Price

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

HSF1 (heat-shock factor 1) is the master regulator of the heat-shock response; however, it is also activated by cancer-associated stresses and supports cellular transformation and cancer progression. We examined the role of HSF1 in relation to cancer cell clonogenicity, an important attribute of cancer cells. Ectopic expression or HSF1 knockdown demonstrated that HSF1 positively regulated cancer cell clonogenic growth. Furthermore, knockdown of mutant p53 indicated that HSF1 actions were mediated via a mutant p53-dependent mechanism. To examine this relationship more specifically, we ectopically co-expressed mutant p53R273H and HSF1 in the human mammary epithelial cell line MCF10A. Surprisingly, within this cellular context, HSF1 inhibited clonogenicity. However, upon specific knockdown of endogenous wild-type p53, leaving mutant p53R273H expression intact, HSF1 was observed to greatly enhance clonogenic growth of the cells, indicating that HSF1 suppressed clonogenicity via wild-type p53. To confirm this we ectopically expressed HSF1 in non-transformed and H-RasV12-transformed MCF10A cells. As expected, HSF1 significantly reduced clonogenicity, altering wild-type p53 target gene expression levels consistent with a role of HSF1 increasing wild-type p53 activity. In support of this finding, knockdown of wild-type p53 negated the inhibitory effects of HSF1 expression. We thus show that HSF1 can affect clonogenic growth in a p53 context-dependent manner, and can act via both mutant and wild-type p53 to bring about divergent effects upon clonogenicity. These findings have important implications for our understanding of HSF1 s divergent roles in cancer cell growth and survival as well as its disparate effect on mutant and wild-type p53.
Original languageEnglish
Pages (from-to)321 - 329
Number of pages9
JournalBiochemical Journal
Volume452
Issue number2
DOIs
Publication statusPublished - 2013

Cite this

Nguyen, Chau Hoang ; Lang, Benjamin James ; Chai, Ryan Chau Chia ; Vieusseux, Jessica Louise ; Kouspou, Michelle Maria ; Price, John Timothy. / Heat-shock factor 1 both positively and negatively affects cellular clonogenic growth depending on p53 status. In: Biochemical Journal. 2013 ; Vol. 452, No. 2. pp. 321 - 329.
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abstract = "HSF1 (heat-shock factor 1) is the master regulator of the heat-shock response; however, it is also activated by cancer-associated stresses and supports cellular transformation and cancer progression. We examined the role of HSF1 in relation to cancer cell clonogenicity, an important attribute of cancer cells. Ectopic expression or HSF1 knockdown demonstrated that HSF1 positively regulated cancer cell clonogenic growth. Furthermore, knockdown of mutant p53 indicated that HSF1 actions were mediated via a mutant p53-dependent mechanism. To examine this relationship more specifically, we ectopically co-expressed mutant p53R273H and HSF1 in the human mammary epithelial cell line MCF10A. Surprisingly, within this cellular context, HSF1 inhibited clonogenicity. However, upon specific knockdown of endogenous wild-type p53, leaving mutant p53R273H expression intact, HSF1 was observed to greatly enhance clonogenic growth of the cells, indicating that HSF1 suppressed clonogenicity via wild-type p53. To confirm this we ectopically expressed HSF1 in non-transformed and H-RasV12-transformed MCF10A cells. As expected, HSF1 significantly reduced clonogenicity, altering wild-type p53 target gene expression levels consistent with a role of HSF1 increasing wild-type p53 activity. In support of this finding, knockdown of wild-type p53 negated the inhibitory effects of HSF1 expression. We thus show that HSF1 can affect clonogenic growth in a p53 context-dependent manner, and can act via both mutant and wild-type p53 to bring about divergent effects upon clonogenicity. These findings have important implications for our understanding of HSF1 s divergent roles in cancer cell growth and survival as well as its disparate effect on mutant and wild-type p53.",
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Heat-shock factor 1 both positively and negatively affects cellular clonogenic growth depending on p53 status. / Nguyen, Chau Hoang; Lang, Benjamin James; Chai, Ryan Chau Chia; Vieusseux, Jessica Louise; Kouspou, Michelle Maria; Price, John Timothy.

In: Biochemical Journal, Vol. 452, No. 2, 2013, p. 321 - 329.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Heat-shock factor 1 both positively and negatively affects cellular clonogenic growth depending on p53 status

AU - Nguyen, Chau Hoang

AU - Lang, Benjamin James

AU - Chai, Ryan Chau Chia

AU - Vieusseux, Jessica Louise

AU - Kouspou, Michelle Maria

AU - Price, John Timothy

PY - 2013

Y1 - 2013

N2 - HSF1 (heat-shock factor 1) is the master regulator of the heat-shock response; however, it is also activated by cancer-associated stresses and supports cellular transformation and cancer progression. We examined the role of HSF1 in relation to cancer cell clonogenicity, an important attribute of cancer cells. Ectopic expression or HSF1 knockdown demonstrated that HSF1 positively regulated cancer cell clonogenic growth. Furthermore, knockdown of mutant p53 indicated that HSF1 actions were mediated via a mutant p53-dependent mechanism. To examine this relationship more specifically, we ectopically co-expressed mutant p53R273H and HSF1 in the human mammary epithelial cell line MCF10A. Surprisingly, within this cellular context, HSF1 inhibited clonogenicity. However, upon specific knockdown of endogenous wild-type p53, leaving mutant p53R273H expression intact, HSF1 was observed to greatly enhance clonogenic growth of the cells, indicating that HSF1 suppressed clonogenicity via wild-type p53. To confirm this we ectopically expressed HSF1 in non-transformed and H-RasV12-transformed MCF10A cells. As expected, HSF1 significantly reduced clonogenicity, altering wild-type p53 target gene expression levels consistent with a role of HSF1 increasing wild-type p53 activity. In support of this finding, knockdown of wild-type p53 negated the inhibitory effects of HSF1 expression. We thus show that HSF1 can affect clonogenic growth in a p53 context-dependent manner, and can act via both mutant and wild-type p53 to bring about divergent effects upon clonogenicity. These findings have important implications for our understanding of HSF1 s divergent roles in cancer cell growth and survival as well as its disparate effect on mutant and wild-type p53.

AB - HSF1 (heat-shock factor 1) is the master regulator of the heat-shock response; however, it is also activated by cancer-associated stresses and supports cellular transformation and cancer progression. We examined the role of HSF1 in relation to cancer cell clonogenicity, an important attribute of cancer cells. Ectopic expression or HSF1 knockdown demonstrated that HSF1 positively regulated cancer cell clonogenic growth. Furthermore, knockdown of mutant p53 indicated that HSF1 actions were mediated via a mutant p53-dependent mechanism. To examine this relationship more specifically, we ectopically co-expressed mutant p53R273H and HSF1 in the human mammary epithelial cell line MCF10A. Surprisingly, within this cellular context, HSF1 inhibited clonogenicity. However, upon specific knockdown of endogenous wild-type p53, leaving mutant p53R273H expression intact, HSF1 was observed to greatly enhance clonogenic growth of the cells, indicating that HSF1 suppressed clonogenicity via wild-type p53. To confirm this we ectopically expressed HSF1 in non-transformed and H-RasV12-transformed MCF10A cells. As expected, HSF1 significantly reduced clonogenicity, altering wild-type p53 target gene expression levels consistent with a role of HSF1 increasing wild-type p53 activity. In support of this finding, knockdown of wild-type p53 negated the inhibitory effects of HSF1 expression. We thus show that HSF1 can affect clonogenic growth in a p53 context-dependent manner, and can act via both mutant and wild-type p53 to bring about divergent effects upon clonogenicity. These findings have important implications for our understanding of HSF1 s divergent roles in cancer cell growth and survival as well as its disparate effect on mutant and wild-type p53.

UR - http://www.biochemj.org/bj/452/0321/4520321.pdf

U2 - 10.1042/BJ20130098

DO - 10.1042/BJ20130098

M3 - Article

VL - 452

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EP - 329

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

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