Abstract 1829: HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation

Abstract AMP-activated protein kinase (AMPK), a key cellular metabolic sensor, suppresses anabolic pathways, including lipogenesis and cholesterol biosynthesis, thereby maintaining energy homeostasis. Heat shock factor 1 (HSF1) is the master regulator of the evolutionarily conserved proteotoxic stress response (PSR), thereby preserving proteostasis in the face of environmental insults. In contrast to its beneficial role in enhancing survival under proteotoxic stress, it has been demonstrated that HSF1 acts as a potent pro-oncogenic factor. Our previous study has shown that metabolic stressors, via AMPK activation, inactivate HSF1 and disrupt proteostasis to suppress tumor growth. Interestingly, our new study now reveals that HSF1, in reciprocal, also suppresses AMPK activation. HSF1 does so independently of its canonical transcriptional action. Furthermore, Hsf1 deficiency promotes the interactions between AMPK and LKB1, a key upstream kinase activating AMPK. Congruent with the suppression of lipogenesis by AMPK, Hsf1 deficiency depletes cellular lipid content and reduces body fat mass in mice. Importantly, these defects can be largely rescued by either pharmacological or genetic inhibition of AMPK. At the molecular level, Hsf1 deficiency leads to inactivation of acetyl-CoA Carboxylase (ACC) and sterol regulatory element-binding transcription factor 1c (SREBP1c), both of which are key players in de novo lipogenesis. In addition to impaired lipogenesis, Hsf1-deficient cells and mice display reduced cholesterol levels. Of particular interest, this defect leads to impaired cholesteroylation of sonic hedgehog (SHH), the best known signaling molecule undergoing this covalent modification. In consequence, SHH secreted by HSF1-deficient cells are less potent in activating its downstream signaling cascade, indicated by reduced DNA binding of GLI1, a transcription factor responding to activation of SHH signaling. Conversely, HSF1 overexpression increases the lipid content, cholesterol levels and the amount of cholesteroylated SHH proteins in xenografted melanomas. Taken together, our results reveal that HSF1, through AMPK suppression, promotes lipogenesis, cholesterol biosynthesis and protein lipidation, thereby supporting malignant growth. Citation Format: Kuo-Hui Su, Chengkai Dai. HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1829.