IER5 generates a novel hypo-phosphorylated active form of HSF1 and contributes to tumorigenesis

Yoshinori Asano; Tatsuya Kawase; Atsushi Okabe; Shuichi Tsutsumi; Hitoshi Ichikawa; Satoko Tatebe; Issay Kitabayashi; Fumio Tashiro; Hideo Namiki; Tadashi Kondo; Kentaro Semba; Hiroyuki Aburatani; Yoichi Taya; Hitoshi Nakagama; Rieko Ohki

doi:10.1038/srep19174

IER5 generates a novel hypo-phosphorylated active form of HSF1 and contributes to tumorigenesis

Sci Rep. 2016 Jan 12:6:19174. doi: 10.1038/srep19174.

Authors

Yoshinori Asano^{1

2}, Tatsuya Kawase^{3

4}, Atsushi Okabe⁵, Shuichi Tsutsumi⁵, Hitoshi Ichikawa⁶, Satoko Tatebe⁴, Issay Kitabayashi⁷, Fumio Tashiro⁴, Hideo Namiki², Tadashi Kondo¹, Kentaro Semba², Hiroyuki Aburatani⁵, Yoichi Taya³, Hitoshi Nakagama⁸, Rieko Ohki¹

Affiliations

¹ Division of Rare Cancer Research, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
² Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo, 169-8555, Japan.
³ Radiobiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
⁴ Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Niijuku 6-3-1, Katsushika-ku, Tokyo 125-8585, Japan.
⁵ Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
⁶ Department of Clinical Genomics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
⁷ Division of Hematological Malignancy, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
⁸ Division of Cancer Development System, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.

Abstract

The transcription factors HSF1 and p53 both modulate the stress response, thereby protecting and facilitating the recovery of stressed cells, but both have the potential to promote tumor development. Here we show that a p53 target gene, IER5, encodes an activator of HSF1. IER5 forms a ternary complex with HSF1 and the phosphatase PP2A, and promotes the dephosphorylation of HSF1 at numbers of serine and threonine residues, generating a novel, hypo-phosphorylated active form of HSF1. IER5 is also transcriptionally upregulated in various cancers, although this upregulation is not always p53-dependent. The IER5 locus is associated with a so-called super enhancer, frequently associated with hyperactivated oncogenes in cancer cell lines. Enhanced expression of IER5 induces abnormal HSF1 activation in cancer cells and contributes to the proliferation of these cells under stressed conditions. These results reveal the existence of a novel IER5-mediated cancer regulation pathway that is responsible for the activation of HSF1 observed in various cancers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / metabolism*
DNA Damage
DNA-Binding Proteins / metabolism*
Enhancer Elements, Genetic
Gene Expression
Gene Expression Regulation
Heat Shock Transcription Factors
Humans
Immediate-Early Proteins / genetics*
Immediate-Early Proteins / metabolism
Multigene Family
Multiprotein Complexes
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / mortality
Neoplasms / pathology
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Phosphorylation
Prognosis
Promoter Regions, Genetic
Protein Binding
Protein Phosphatase 2 / metabolism
Signal Transduction
Transcription Factors / metabolism*
Transcription, Genetic
Tumor Suppressor Protein p53 / metabolism

Substances

DNA-Binding Proteins
HSF1 protein, human
Heat Shock Transcription Factors
IER5 protein, human
Immediate-Early Proteins
Multiprotein Complexes
Nuclear Proteins
Transcription Factors
Tumor Suppressor Protein p53
Protein Phosphatase 2