Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment

Abstract

POU4F2/Brn-3b transcription factor (referred to as Brn-3b) is elevated in >60% of breast cancers and profoundly alters growth and behaviour of cancer cells by regulating distinct subsets of target genes. Previous studies showed that Brn-3b was required to maximally transactivate small heat shock protein, HSPB1/Hsp-27 (referred to as , and consequently, Brn-3b expression correlated well with Hsp27 levels in human breast biopsies. In these studies, we showed that Brn-3b is increased in MCF7 breast cancer cells that survive following treatment with chemotherapeutic drug doxorubicin (Dox) with concomitant increases in Hsp-27 expression. Targeting of Brn3b using short interfering RNA reduced Hsp-27 in Doxtreated cells, suggesting that Brn-3b regulates Hsp-27 expression under these conditions. Wound healing assays showed increased Brn-3b in Dox-treated migratory cells that also express Hsp-27. Interestingly, Hsp-27 phosphorylation and cellular localisation are also significantly altered at different times following Dox treatment. Thus, phosphoHsp-27 (p-Hsp27) protein displayed widespread distribution after 24 hrs of Dox treatment but was restricted to the nucleus after 5 days. However, in drug-resistant cells (grown in Dox for >1 month), p-Hsp-27 was excluded from nuclei and most of the cytoplasm and appeared to be associated with the cell membrane. Studies to determine how this protein promotes survival and migration in breast cancer cells showed that the protective effects were conferred by unphosphorylated Hsp-27 protein.

Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

“…Both Hsp27 and Hsp70 (and other HSPs) can block apoptosis therefore it is complicated to maintain the fine tuning in HSP expression levels to allow the drugs to effectively kill cancer cells. In line with this, Fujita et al (2011) reported in MCF-7 cells that survived to doxorubicin that the POU4F2/Brn-3b transcription factor is increased with concomitant increases in Hsp27 expression. The POU4F2/Brn-3b transcription factor is required to maximally trans -activate Hsp27 and is elevated in >60% of breast cancers altering growth and behavior of cancer cells by regulating distinct subsets of target genes.…”

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study

“…In breast cancer, POU4F2 can repress BRCA1 expression [36] and interact with estrogen receptor alpha to enhance its activity [35]. POU4F2 can also induce the expression of CCD1 and CDK4 in the context of proliferation and cell cycle progression [34,37], confer migratory and multidrug resistance properties to breast cancer in in vivo models [38], and cooperate with TP53 to increase transcription of pro-apoptotic genes [39]. Importantly, growth factors like the epidermal growth factor (EGF) can stimulate the activity of the POU4F2 promoter and subsequently its mRNA and protein expression, which in turn can affect POU4F2 target genes influencing growth and behavior of cancer cells.…”

Involvement of small heat shock proteins, trehalose, and lipids in the thermal stress management in Schizosaccharomyces pombe

“…or higher Electronic supplementary material The online version of this article (doi:10.1007/s12192-015-0662-4) contains supplementary material, which is available to authorized users. eukaryotes (Adamska and Kloppstech 1991;Eisenberg-Domovich et al 1994;Heckathorn et al 1998;Bausero et al 2005;de Miguel et al 2008;Fujita et al 2011). Whether different Hsps interact only with membrane proteins, only with membrane lipids, or with both remains to be explored.…”