Abstract

CLL is a disease characterized by chromosomal deletions, acquired copy number changes and aneuploidy. Recent studies have shown that overexpression of Heat Shock Factor (HSF) 1 in aneuploid tumor cells can overcome deficiencies in heat shock protein (HSP) 90-mediated protein folding and restore protein homeostasis. Interestingly, several independent studies have demonstrated that HSF1 expression and activity also affects the chaperoning of HSP90 kinase clients, although the mechanism underlying this observation is unclear. Here, we determined how HSF1 regulates HSP90 function using CLL as a model system. We report that HSF1 is overexpressed in CLL and treatment with triptolide (a small molecule inhibitor of HSF1) induces apoptosis in cultured and primary CLL B-cells. We demonstrate that knockdown of HSF1 or its inhibition with triptolide results in the reduced association of HSP90 with its kinase co-chaperone cell division cycle 37 (CDC37), leading to the partial depletion of HSP90 client kinases, Bruton's Tyrosine Kinase (BTK), c-RAF and cyclin-dependent kinase 4 (CDK4). Treatment with triptolide or HSF1 knockdown disrupts the cytosolic complex between HSF1, p97, HSP90 and the HSP90 deacetylase- Histone deacetylase 6 (HDAC6). Consequently, HSF1 inhibition results in HSP90 acetylation and abrogation of its chaperone function. Finally, tail vein injection of Mec-1 cells into Rag2-/-IL2Rγc-/- mice followed by treatment with minnelide (a pro-drug of triptolide), reduced leukemia, increased survival and attenuated HSP90-dependent survival signaling in vivo. In conclusion, our study provides a strong rationale to target HSF1 and test the activity of minnelide against human CLL.

Highlights

  • Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in the western hemisphere [1, 2]

  • We report that Heat Shock Factor 1 (HSF1) is overexpressed in CLL and treatment with triptolide induces apoptosis in cultured and primary CLL B-cells

  • We demonstrate for the first time that treatment with triptolide or depletion of cellular HSF1 levels disrupts the association of HSF1 with components of the cytosolic repressive complex comprising HSF1-HSP90HDAC6-p97, resulting in the acetylation of HSP90

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Summary

Introduction

Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in the western hemisphere [1, 2]. A recent study has reported that overexpression of Heat Shock Factor 1 (HSF1) restores the ability of aneuploid cells to maintain protein homeostasis [6, 7]. HSF1, a stress-inducible transcription factor, exists in a repressive complex comprising HSP90, HDAC6 and p97 (a segregase with ATPase activity) [8]. Accumulation of misfolded proteins, or malignant transformation, results in the dissociation of HSF1 from the repressive complex. Activated HSF1 up-regulates the transcription of HSPs, which ameliorate misfolded proteininduced proteotoxic stress. HSF1-induced heat shock proteins (HSPs) promote survival of cancer cells following exposure to chemotherapeutic agents and have been implicated in conferring resistance to chemotherapy as well as promotion of tumor growth and metastasis [9,10,11]

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