HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways
HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways
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DOI：
10.3390/cancers11091363
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发表时间：
2019-09-01
期刊：
影响因子：
5.2
通讯作者：
Lim, Ji-Hong
中科院分区：
文献类型：
--
作者：
Kang, Hyeji;Oh, Taerim;Lim, Ji-Hong
热休克因子1（Heat shock factor 1，HSF 1）是细胞对热、蛋白质毒性应激、代谢应激、活性氧和重金属等多种应激反应的重要转录因子。HSF 1促进癌症的发展和进展，并且在多种类型的癌症中经常观察到HSF 1水平的增加。在各种癌症中观察到甲羟戊酸和胆固醇生物合成途径的活性增加，这对癌症生长和进展非常重要。然而，HSF 1在甲羟戊酸和胆固醇生物合成途径中的功能作用尚未研究。在这里，我们证明了通过H-Ras（V12）的过表达激活RAS-MAPK信号传导增加了HSF 1的表达和胆固醇生物合成途径。此外，还发现HSF 1的活化增加胆固醇的生物合成。因此，通过药理学抑制剂KRIBB 11和短发夹RNA（shRNA）抑制HSF 1逆转了H-Ras（V12）诱导的胆固醇生物合成。从肝细胞癌（HCC）治疗的治疗应用的角度来看，HSF 1抑制显示出敏感的辛伐他汀在HCC细胞中的抗增殖作用。总的来说，我们的研究结果表明，HSF 1是一个潜在的目标，他汀类药物为基础的肝癌治疗。
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-Ras(V12) 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-Ras(V12)-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.