Project Summary
There is an urgent need to develop new therapeutic options for carcinogenesis. The goal of this
proposal is to help fulfill this need by shedding new light on the molecular pathways driving
tumorigenesis. Recently published data reveals pro-oncogenic activity of heat shock factor 1
(HSF1), the master regulator of the heat shock response, and indicate that AMP-activated protein
kinase (AMPK) phosphorylates S121 of HSF1, inactivating it and thereby disrupting malignancy.
Whether HSF1 reciprocally impacts AMPK has yet to be explored. Preliminary data indicate that
HSF1 physically interacts with and inhibits AMPK independently of HSF1 transcriptional activity
at steady state. Genetic deletion of HSF1 suppresses cellular lipogenesis, cholesterol synthesis,
protein cholesteroylation (important for the stability and activity of the target protein), and fat mass
in mixed background mice through AMPK. Overexpression of HSF1 promotes a lipogenic
phenotype and tumor growth. These results suggest that HSF1 transcriptionally independently
inhibits AMPK to promote lipogenic phenotype of tumor growth. The proposed project addresses
this hypothesis by pursuing two Specific Aims. Aim 1: To elucidate the detailed mechanism of
HSF1-mediated AMPK suppression. First, a high-resolution library of HSF1 peptides will be used
to study AMPK inhibition in in vitro and in vivo models. Second, a biophysical method will be used
to determine the impact of HSF1 on AMPK conformation. Aim 2: To test the hypothesis that HSF1
supports lipid biosynthesis in tumor growth. First, how exactly HSF1 regulates AMPK-mediated
lipogenesis, cholesterol synthesis, and protein cholesteroylation will be determined. Second, the
mechanism will be studied in inbred mice with AMPK suppression. Third, the transcriptionally
independent activity of HSF1 and its associated AMPK-regulated lipid and cholesterol metabolism
will be studied in a human melanoma xenograft model. This proposal is significant because it will
provide a deeper understanding of proteostasis in tumor progression, investigate a novel
therapeutic target for cancer treatment, and identify a gene expression signature that informs
clinical progression and outcomes. The project is conceptually and technically innovative as it will:
i) examine the role of HSF1 as a novel inhibitor for AMPK, ii) investigate protein cholesteroylation
by HSF1 and AMPK, and iii) develop endogenous HSF1 as a novel prognostic indicator for cancer
patient survival. The proposal will provide a stepping stone to enable the candidate to establish
an independent research career and ultimately become a leader in the field of carcinogenesis,
contributing to breakthrough discoveries that lead to improved treatment strategies.