Phosphorylation of HSF1 at serine 326 residue is related to the maintenance of gynecologic cancer stem cells through expression of HSP27

// Kazuyo Yasuda 1 , Yoshihiko Hirohashi 1 , Tasuku Mariya 1, 2 , Aiko Murai 1 , Yuta Tabuchi 1, 2 , Takafumi Kuroda 2 , Hiroki Kusumoto 1 , Akari Takaya 1 , Eri Yamamoto 1 , Terufumi Kubo 1 , Munehide Nakatsugawa 1 , Takayuki Kanaseki 1 , Tomohide Tsukahara 1 , Yasuaki Tamura 1 , Hiroshi Hirano 3 , Tadashi Hasegawa 3 , Tsuyoshi Saito 2 , Noriyuki Sato 1 , Toshihiko Torigoe 1 1 Department of Pathology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan 2 Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan 3 Department of Surgical Pathology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan Correspondence to: Toshihiko Torigoe, email: torigoe@sapmed.ac.jp Yoshihiko Hirohashi, email: hirohash@sapmed.ac.jp Keywords: gynecological cancer, cancer stem cell, stress response, HSP27, HSF1 Received: February 10, 2016      Accepted: March 10, 2017      Published: March 18, 2017 ABSTRACT Cancer stem-like cells (CSCs)/ cancer-initiating cells (CICs) are defined by their higher tumor-initiating ability, self-renewal capacity and differentiation capacity. CSCs/CICs are resistant to several therapies including chemotherapy and radiotherapy. CSCs/CICs thus are thought to be responsible for recurrence and distant metastasis, and elucidation of the molecular mechanisms of CSCs/CICs are essential to design CSC/CIC-targeting therapy. In this study, we analyzed the molecular aspects of gynecological CSCs/CICs. Gynecological CSCs/CICs were isolated as ALDH1 high cell by Aldefluor assay. The gene expression profile of CSCs/CICs revealed that several genes related to stress responses are preferentially expressed in gynecological CSCs/CICs. Among the stress response genes, a small heat shock protein HSP27 has a role in the maintenance of gynecological CSCs/CICs. The upstream transcription factor of HSP27, heat shock factior-1 (HSF1) was activated by phosphorylation at serine 326 residue (pSer326) in CSCs/CICs, and phosphorylation at serine 326 residue is essential for induction of HSP27. Immunohistochemical staining using clinical ovarian cancer samples revealed that higher expressions of HSF1 pSer326 was related to poorer prognosis. These findings indicate that activation of HSF1 at Ser326 residue and transcription of HSP27 is related to the maintenance of gynecological CSCs/CICs.