HSF1 regulation of β-catenin in mammary cancer cells through control of HuR/elavL1 expression

Oncogene. 2015 Apr 23;34(17):2178-2188. doi: 10.1038/onc.2014.177. Epub 2014 Jun 23.

Abstract

There is now compelling evidence to indicate a place for heat shock factor 1 (HSF1) in mammary carcinogenesis, tumour progression and metastasis. Here we have investigated a role for HSF1 in regulating the expression of the stem cell renewal factor β-catenin in immortalized human mammary epithelial and carcinoma cells. We found HSF1 to be involved in regulating the translation of β-catenin, by investigating effects of gain and loss of HSF1 on this protein. Interestingly, although HSF1 is a potent transcription factor, it was not directly involved in regulating levels of β-catenin mRNA. Instead, our data suggest a complex role in translational regulation. HSF1 was shown to regulate levels of the RNA-binding protein HuR that controlled β-catenin translation. An extra complexity was added to this scenario when it was shown that the long non-coding RNA molecule lincRNA-p21, known to be involved in β-catenin mRNA (CTNNB1) translational regulation, was controlled by HSF1 repression. We have shown previously that HSF1 was positively regulated through phosphorylation by mammalian target of rapamycin (mTOR) kinase on a key residue, serine 326, essential for transcriptional activity. In this study, we found that mTOR knockdown not only decreased HSF1-S326 phosphorylation in mammary cells, but also decreased β-catenin expression through a mechanism requiring HuR. Our data point to a complex role for HSF1 in the regulation of HuR and β-catenin expression that may be significant in mammary carcinogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • ELAV Proteins / genetics
  • ELAV Proteins / metabolism*
  • ELAV-Like Protein 1
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Heat Shock Transcription Factors
  • Humans
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • beta Catenin / biosynthesis*
  • beta Catenin / genetics

Substances

  • CTNNB1 protein, human
  • DNA-Binding Proteins
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Neoplasm Proteins
  • RNA, Long Noncoding
  • Transcription Factors
  • beta Catenin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases