Department of Medical Oncology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650000, China.
Faculty of Medicine, Kunming University of Science and Technology, Kunming, 650000, China.
Mol Cell Biochem. 2023 May;478(5):1141-1150. doi: 10.1007/s11010-022-04582-2. Epub 2022 Oct 13.
Heat shock factors (HSFs) are a family of transcription factors, composed of HSF1, HSF2, and HSF4, to regulate cell stress reaction for maintaining cellular homeostasis in response to adverse stimuli. Recent studies have disclosed the roles of HSF1 and HSF2 in modulating tumor development, including colorectal cancer (CRC). However, HSF4, which is closely associated with pathology of congenital cataracts, remains less studied in tumors. In this study, we aimed to describe the regulatory effects of HSF4 and underlying molecular mechanism in CRC progression. By bioinformatic analysis of TCGA database and TMA-IHC assay, we identified that the expression of HSF4 was significantly upregulated in CRCs compared with normal colonic tissues and was a prognostic factor of poor outcomes of CRC patients. Function assays, including CCK-8, colony formation, transwell assays, and xenografted mouse model, were employed to verify that HSF4 promoted cell growth, colony formation, invasion of CRC cells in vitro, and tumor growth in vivo as a potential oncogenic factor. Mechanistically, results of Chromatin immunoprecipitation (ChIP) and immunoblotting assays revealed that HSF4 associated directly to MET promoter to enhance expression of c-MET, a well-known oncogene in multiple cancers, thus fueling the activity of downstream ERK1/2 and AKT signaling pathways. In further rescue experiments, restoration of c-MET expression abolished inhibitory cell growth and invasion induced by downregulated HSF4 expression. To sum up, our findings describe a crucial role of HSF4 in CRC progression by enhancing activity of c-MET and downstream ERK1/2 and AKT signaling pathways, and highlight HSF4 as a potential therapeutic target for anti-CRC treatment.
热休克因子（HSFs）是一类转录因子家族，由 HSF1、HSF2 和 HSF4 组成，用于调节细胞应激反应，以维持细胞内稳态，应对不利刺激。最近的研究揭示了 HSF1 和 HSF2 在调节肿瘤发生中的作用，包括结直肠癌（CRC）。然而，与先天性白内障病理密切相关的 HSF4 在肿瘤中的研究较少。在这项研究中，我们旨在描述 HSF4 的调节作用及其在 CRC 进展中的潜在分子机制。通过 TCGA 数据库的生物信息学分析和 TMA-IHC 检测，我们确定 HSF4 在 CRC 中的表达明显高于正常结肠组织，并且是 CRC 患者预后不良的一个预后因素。功能检测，包括 CCK-8、集落形成、Transwell 检测和异种移植小鼠模型，用于验证 HSF4 作为潜在致癌因子促进 CRC 细胞的体外生长、集落形成、侵袭和体内肿瘤生长。机制上，染色质免疫沉淀（ChIP）和免疫印迹检测结果表明，HSF4 直接与 MET 启动子结合，增强了 c-MET 的表达，c-MET 是多种癌症中的一种已知致癌基因，从而激活了下游 ERK1/2 和 AKT 信号通路。在进一步的挽救实验中，恢复 c-MET 的表达可消除下调 HSF4 表达引起的抑制细胞生长和侵袭作用。总之，我们的研究结果描述了 HSF4 通过增强 c-MET 及其下游 ERK1/2 和 AKT 信号通路的活性在 CRC 进展中的关键作用，并强调了 HSF4 作为抗 CRC 治疗的潜在治疗靶点。
