Targeting HSF1 disrupts HSP90 chaperone function in chronic lymphocytic leukemia

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Chronic lymphocytic leukemia (CLL) is characterized by genetic abnormalities including aneuploidy.
• Heat Shock Factor 1 (HSF1) overexpression in aneuploid cells can compensate for impaired heat shock protein (HSP) 90 function.
• The precise mechanism by which HSF1 influences HSP90 client protein chaperoning remains unclear.

Purpose of the Study:

• To elucidate how HSF1 regulates HSP90 function in the context of CLL.
• To investigate the therapeutic potential of targeting HSF1 in CLL.

Main Methods:

• HSF1 expression levels were analyzed in CLL.
• The effects of HSF1 inhibition using triptolide on CLL cells were assessed in vitro and in vivo.
• Protein-protein interactions involving HSF1, HSP90, and its co-chaperones/clients were examined.
• HSP90 acetylation and chaperone activity were evaluated upon HSF1 inhibition.

Main Results:

• HSF1 is overexpressed in CLL; triptolide treatment induced apoptosis in CLL cells.
• HSF1 inhibition reduced HSP90 association with CDC37, leading to depletion of HSP90 client kinases (BTK, c-RAF, CDK4).
• Triptolide disrupted the cytosolic complex of HSF1, p97, HSP90, and HDAC6, causing HSP90 acetylation and impaired chaperone function.
• In vivo, minnelide treatment reduced leukemia burden and increased survival in a mouse model.

Conclusions:

• HSF1 plays a critical role in maintaining HSP90 chaperone function in CLL.
• Targeting HSF1 with inhibitors like triptolide or its prodrug minnelide demonstrates therapeutic efficacy against CLL.
• These findings provide a strong rationale for developing HSF1-targeted therapies for human CLL.