Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state [ChIP-Seq]. Homo sapiens

A unifying characteristic of aggressive cancers is a profound anabolic shift in metabolism to enable sustained proliferation and biomass expansion. The ribosome is centrally situated to sense metabolic states but whether it impacts systems that promote cellular survival is unknown. Here, through integrated chemical-genetic analyses, we find that a dominant transcriptional effect of blocking protein translation in cancer cells is complete inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for tumorigenesis. Translational flux through the ribosome reshapes the transcriptional landscape and links the fundamental anabolic processes of protein production and energy metabolism with HSF1 activity. Targeting this link deprives cancer cells of their energy and chaperone armamentarium thereby rendering the malignant phenotype unsustainable. Overall design: We used ChIP-Seq to examine affect of rocaglates and cycloheximide on HSF1 genomic occupancy in MCF7 and M0-91 cancer cells.

侵袭性癌症的共同特征是代谢发生显著的合成代谢重编程，以支持细胞持续增殖与生物量扩增。核糖体在感知细胞代谢状态中发挥核心作用，但其是否可调控促进细胞存活的信号通路，目前尚不明确。
本研究通过整合化学遗传学分析，发现阻断癌细胞内蛋白质翻译过程的主要转录调控效应，是完全灭活热休克因子1（heat shock factor 1, HSF1）——这是一种兼具多种功能的转录调控因子，可调控热休克应答以及肿瘤发生所必需的诸多细胞过程。核糖体的翻译流可重塑细胞的转录组全貌，并将蛋白质合成与能量代谢这两大基础合成代谢过程，与HSF1的活性建立关联。靶向干预这一关联，可剥夺癌细胞的能量供给与分子伴侣储备，进而使恶性表型无法维持。
实验整体设计：我们采用染色质免疫共沉淀测序（ChIP-Seq），检测罗卡格类化合物与放线菌酮对MCF7及M0-91癌细胞中HSF1基因组结合位点占有率的影响。