Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Cancer Med. 2024 Sep;13(17):e70157. doi: 10.1002/cam4.70157.
Heat shock transcription factors (HSFs) play crucial roles in the development of malignancies. However, the specific roles of HSFs in hepatocellular carcinoma (HCC) have yet to be fully elucidated.
To explore the involvement of the HSF family, particularly HSF1, in the progression and prognosis of HCC.
MATERIALS & METHODS: We conducted a thorough analysis of HSF expression and copy number variations across various cancer datasets. Specifically focusing on HSF1, we examined its expression levels and prognostic implications in HCC. In vitro and in vivo experiments were carried out to evaluate the impact of HSF1 on liver cancer cell proliferation. Additionally, we utilized CUT&Tag, H3K27 acetylation enrichment, and RNA sequencing (RNA-seq) to investigate the super-enhancer (SE) regulatory landscapes of HSF1 in liver cancer cell lines.
HSF1 expression is elevated in HCC and is linked to poor prognosis in several datasets. HSF1 stimulates liver cancer cell proliferation both in vitro and in vivo, partly through modulation of H3K27ac levels, influencing enhancer distribution. Mechanistically, our findings demonstrate that HSF1 transcriptionally activates MYCN expression by binding to its promoter and SE elements, thereby promoting liver cancer cell proliferation. Moreover, increased MYCN expression was detected in HCC tumors and correlated with unfavorable patient outcomes.
Our study sheds light on previously unexplored aspects of HSF1 biology, identifying it as a transcription factor capable of shaping the epigenetic landscape in the context of HCC. Given HSF1's potential as an epigenetic regulator, targeting the HSF1-MYCN axis could open up new therapeutic possibilities for HCC treatment.
The HSF1-MYCN axis constitutes a transcription-dependent regulatory mechanism that may function as both a prognostic indicator and a promising therapeutic target in liver cancer. Further exploration of this axis could yield valuable insights into novel treatment strategies for HCC.
热休克转录因子（HSFs）在恶性肿瘤的发展中起着至关重要的作用。然而，HSFs 在肝细胞癌（HCC）中的具体作用尚未完全阐明。
探讨 HSF 家族，特别是 HSF1，在 HCC 进展和预后中的作用。
我们对各种癌症数据集进行了 HSF 表达和拷贝数变异的全面分析。特别关注 HSF1，我们研究了其在 HCC 中的表达水平及其预后意义。进行了体外和体内实验，以评估 HSF1 对肝癌细胞增殖的影响。此外，我们利用 CUT&Tag、H3K27 乙酰化富集和 RNA 测序（RNA-seq）研究了 HSF1 在肝癌细胞系中的超级增强子（SE）调控景观。
HSF1 在 HCC 中表达上调，并且在几个数据集中与预后不良相关。HSF1 在体外和体内均刺激肝癌细胞增殖，部分通过调节 H3K27ac 水平影响增强子分布。从机制上讲，我们的研究结果表明，HSF1 通过结合其启动子和 SE 元件转录激活 MYCN 表达，从而促进肝癌细胞增殖。此外，在 HCC 肿瘤中检测到 MYCN 表达增加，并与患者不良预后相关。
我们的研究揭示了 HSF1 生物学的以前未探索的方面，确定 HSF1 是一种能够在 HCC 背景下塑造表观遗传景观的转录因子。鉴于 HSF1 作为表观遗传调节剂的潜力，靶向 HSF1-MYCN 轴可能为 HCC 治疗开辟新的治疗可能性。
HSF1-MYCN 轴构成了一种转录依赖性调节机制，可能作为肝癌的预后指标和有前途的治疗靶点。进一步研究该轴可能为 HCC 的治疗提供有价值的新策略。
