Abstract
Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in multiple types of cancers. Increased activity in the mevalonate and cholesterol biosynthesis pathways, which are very important for cancer growth and progression, is observed in various cancers. However, the functional role of HSF1 in the mevalonate and cholesterol biosynthesis pathways has not yet been investigated. Here, we demonstrated that the activation of RAS-MAPK signaling through the overexpression of H-RasV12 increased HSF1 expression and the cholesterol biosynthesis pathway. In addition, the activation of HSF1 was also found to increase cholesterol biosynthesis. Inversely, the suppression of HSF1 by the pharmacological inhibitor KRIBB11 and short-hairpin RNA (shRNA) reversed H-RasV12-induced cholesterol biosynthesis. From the standpoint of therapeutic applications for hepatocellular carcinoma (HCC) treatment, HSF1 inhibition was shown to sensitize the antiproliferative effects of simvastatin in HCC cells. Overall, our findings demonstrate that HSF1 is a potential target for statin-based HCC treatment.
Highlights
The main source of cholesterol is the diet, intracellular cholesterol levels are carefully regulated by mevalonate (MVA) and the cholesterol biosynthesis pathway, which is tightly controlled by sterol regulatory element-binding protein 2 (SREBP2)-mediated transcriptional programming [3]
We found that increased expression of mevalonate and cholesterol biosynthesis genes caused by simvastatin treatment was significantly reversed in KRIBB11-treated SK-HEP-1 (Figure 1A), PLC/PRF5, and Huh7 (Figure 1B) cells
The reverse effect of KRIBB11 on mevalonate and cholesterol biosynthesis gene expression was increased by lipoprotein depletion (Figure 1C)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common primary liver cancer, and most cases of HCC occur in people with chronic liver disease, such as hepatitis and hepatic steatosis [1,2]. We hypothesized that HSF1 may regulate the mevalonate pathway and cholesterol biosynthesis and promote cell survival and growth. Oncogenic growth signaling, such as in phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and RAS-mitogen-activated protein kinase (MAPK), is triggered to maintain cholesterol homeostasis by activating SREBP-mediated cholesterol biosynthesis [30]. PI3K-AKT and RAS-MAPK growth signaling pathways, considered a hallmark of cancer, is driven by gain-of-function mutations, allowing for cell proliferation and survival and subsequently resulting in the development and progression of multiple types of cancer; the precise molecular mechanism by which RAS-MAPK activates cholesterol biosynthesis is not clearly understood. Our results demonstrate that activated HSF1 via oncogenic RAS-MAPK signaling may be a potential target for overcoming complications arising in statin-based HCC treatment
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