Cellular stress induces cancer stem‐like cells through expression of DNAJB8 by activation of heat shock factor 1

Abstract

In a previous study, we found that DNAJB8, a heat shock protein (HSP) 40 family member is expressed in kidney cancer stem‐like cells (CSC)/cancer‐initiating cells (CIC) and that it has a role in the maintenance of kidney CSC/CIC. Heat shock factor (HSF) 1 is a key transcription factor for responses to stress including heat shock, and it induces HSP family expression through activation by phosphorylation. In the present study, we therefore examined whether heat shock (HS) induces CSC/CIC. We treated the human kidney cancer cell line ACHN with HS, and found that HS increased side population (SP) cells. Western blot analysis and qRT‐PCR showed that HS increased the expression of DNAJB8 and SOX2. Gene knockdown experiments using siRNAs showed that the increase in SOX2 expression and SP cell ratio depends on DNAJB8 and that the increase in DNAJB8 and SOX2 depend on HSF1. Furthermore, treatment with a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, decreased the expression of DNAJB8 and SOX2 and the ratio of SP cells. Taken together, the results indicate that heat shock induces DNAJB8 by activation of HSF1 and induces cancer stem‐like cells.

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…In the same study, DnaJB8 knockout in renal cell carcinoma cells conferred them sensitivity to docetaxel, thus indicating a link between HSP40 and drug resistance intrinsic to CSCs. Notably, an increase in the amounts of the SP cells and SOX2 expression was found in kidney cancer cells being subjected to heat stress; by means of DnaJB8 knockdown with siRNAs, it was shown that the observed effects were due to HSF1-induced DnaJB8 upregulation [131]. The revealed fact that both the accumulation of CSC-like cells (SP cells) and the expression of SOX2 (a transcription factor maintaining the self-renewal of CSCs [2][3][4][5]) are dependent on HSP40 and HSF1 is of importance.…”

“…Similarly, the activating phosphorylation of HSF1 at serine 326 was shown to be critical for the maintenance of gynecologic CSCs, although the researchers explained the effect of the HSF1 activation-triggered induction of HSP27 [171]. However, not HSP27 but members of the HSP40 family, DNAJB8 [131] and DNAJA1 [134], were determined as the critical products of the heat-induced HSF1 activation/HSP expression pathway that conferred the cancer stemness-like properties. Despite some discrepancy (HSP27 vs. HSP40), HSF1 activation and subsequent expression of inducible chaperones (HSPs) in tumor cells clearly promote the CSC phenotype's acquisition.…”

Cancer Antigen Discovery Is Enabled by RNA Sequencing of Highly Purified Malignant and Nonmalignant Cells

“…It is likely that its upregulation in tumors is in response to increased expression of many heat shock proteins, aiding tumor cell proliferation in hostile environments (16). Indeed, other HSP40 family members DNAJB6 and DNAJB8 have both been previously shown to be upregulated in cancer, contributing to cancer-initiating cell maintenance (17)(18)(19). Therapies targeting heat shock proteins and their molecular chaperones are already showing promise in cancer treatment (20).…”

Dnajb8, a target gene of SOX30, is dispensable for male fertility in mice

“…Mutations in DNAJ proteins occur frequently in neurodegenerative diseases, such as cerebellar ataxia, distal hereditary motor neuropathy and Parkinson’s disease ( Koutras & Braun, 2014 ). Nevertheless, DNAJ proteins has also been implicated in tumorogenesis and spermatogenesis ( Kusumoto et al, 2018 ; Meccariello et al, 2014 ; Nishizawa et al, 2012 ). As there are functional differences among the DNAJ proteins, it is unclear whether deficiencies in each DNAJ protein could lead to male infertility.…”