Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer

Cancer Res. 2019 Oct 15;79(20):5233-5244. doi: 10.1158/0008-5472.CAN-19-0063. Epub 2019 Aug 13.

Abstract

Heat shock transcription factor 1 (HSF1) is the master regulator of the proteotoxic stress response, which plays a key role in breast cancer tumorigenesis. However, the mechanisms underlying regulation of HSF1 protein stability are still unclear. Here, we show that HSF1 protein stability is regulated by PIM2-mediated phosphorylation of HSF1 at Thr120, which disrupts the binding of HSF1 to the E3 ubiquitin ligase FBXW7. In addition, HSF1 Thr120 phosphorylation promoted proteostasis and carboplatin-induced autophagy. Interestingly, HSF1 Thr120 phosphorylation induced HSF1 binding to the PD-L1 promoter and enhanced PD-L1 expression. Furthermore, HSF1 Thr120 phosphorylation promoted breast cancer tumorigenesis in vitro and in vivo. PIM2, pThr120-HSF1, and PD-L1 expression positively correlated with each other in breast cancer tissues. Collectively, these findings identify PIM2-mediated HSF1 phosphorylation at Thr120 as an essential mechanism that regulates breast tumor growth and potential therapeutic target for breast cancer. SIGNIFICANCE: These findings identify heat shock transcription factor 1 as a new substrate for PIM2 kinase and establish its role in breast tumor progression.

MeSH terms

  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use
  • Animals
  • Autophagy / drug effects
  • B7-H1 Antigen / biosynthesis*
  • B7-H1 Antigen / genetics
  • Benzylidene Compounds / pharmacology
  • Benzylidene Compounds / therapeutic use
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carboplatin / pharmacology
  • F-Box-WD Repeat-Containing Protein 7 / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / physiology
  • Heat Shock Transcription Factors / antagonists & inhibitors
  • Heat Shock Transcription Factors / genetics
  • Heat Shock Transcription Factors / metabolism*
  • Humans
  • Indazoles / pharmacology
  • Indazoles / therapeutic use
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Protein Stability
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Substrate Specificity
  • Thiazolidinediones / pharmacology
  • Thiazolidinediones / therapeutic use
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

Substances

  • Aminopyridines
  • B7-H1 Antigen
  • Benzylidene Compounds
  • CD274 protein, human
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Indazoles
  • N2-(1H-indazole-5-yl)-N6-methyl-3-nitropyridine-2,6-diamine
  • Neoplasm Proteins
  • PIM2 protein, human
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • SMI-4a compound
  • Thiazolidinediones
  • Carboplatin
  • Protein Serine-Threonine Kinases