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

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 ALDH1high 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.

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

“…The upstream transcription factor of HSP27 is heat shock factor-1 (HSF1) which could be activated by phosphorylation at the serine 326 residue (pSer326) in CSCs/CICs, and the evidence of phosphorylation at pSer326 is considered to be necessary for induction of HSP27. In this very recent paper [62], using human ovarian cancer samples, the authors showed that higher expressions of HSF1 pSer326 and hence transcription of HSP27 is associated with the survival of the CSCs/CICs in these samples. The authors also noted that in the in vitro experiment, both down-regulation and overexpression of HSF1 affect cancersphere-formation under non-stress conditions.…”

“…These results indicate that HSF1 has a role in the maintenance of CSCs/CICs independent of stress, when these cells are matured. Based on the discussed in Section 2.8, HSF1 is only responsible for the transcription of the inducible HSPs, such result in [62] is surprising, and deserves re-confirmation and further study of similar experiments, to find On the other hand, the tumor-suppressor LKB1, which encodes a serinethreonine kinase, directly phosphorylates and activates the 5' adenosine monophosphate-activated protein kinase (AMPK), which is a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in liver, muscle and adipose tissue [63].…”

“…Which mechanism is responsible for the possible impact of HSP27 on the biological behavior of ovarian carcinoma remains to be elucidated". In another clinical study [56] [62]. Note that siRNA is a synthetic RNA duplex designed to specifically target a particular mRNA for degradation.…”

“…We need to target these cells at the advanced/metastatic state of cancer. The studies cited in Section 4.2 suggests that HSP27 may be a good target to develop cancer vaccine at least for a number of cancers such as breast, lung, colon and prostate cancers [62]. Moreover, it was found in [190] that a HSP40 family protein, homolog, subfamily B, member 8 (DNAJB8), which is expressed preferentially in the CSC/CIC population cancer cells, is a novel CSC antigen, particularly in renal cell carcinoma (RCC) and testis cancer.…”

Cancer stem cells as targets for immunotherapy

“…Numb‐1‐ and Notch‐specific T‐cells eliminated luminal CSC/TIC‐like cells in a breast cancer model . In a gynaecological cancer (endometrioid adenocarcinoma), ALDH high cells preferentially expressed Hsp27, the over‐expression of which is associated with poor prognosis . Mitogen‐activated kinase (MAPK)13, pituitary tumour‐transforming gene protein‐binding factor (PTTG1IP), calpain 1 (CAPN1) and ubiquilin 2 (UBQLN2) were also found highly expressed in these cells compared with that in ALDH low cells .…”