Zhai Guijin, Niu Ziping, Jiang Zixin, Zhao Fei, Wang Siyu, Chen Chen, Zheng Wei, Wang Aiyuan, Zang Yong, Han Yanpu, Zhang Kai
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China.
Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong Province 264000, China.
Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2421496121. doi: 10.1073/pnas.2421496121. Epub 2024 Dec 5.
Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. However, how this histone mark acts in cancers remains unexplored due in part to a lack of knowledge about its reader proteins. Here, we observe that cervical cancer (CC) cells undergo metabolic reprogram by which lactate accumulation and thereby boosts histone lactylation, particularly H3K14la. Utilizing a multivalent photoaffinity probe in combination with quantitative proteomics approach, we identify DPF2 as a candidate target of H3K14la. Biochemical studies as well as CUT&Tag analysis reveal that DPF2 is capable of binding to H3K14la and colocalizes with it on promoters of oncogenic genes. Notably, disrupting the DPF2-H3K14la interaction through structure-guided mutation blunts those cancer-related gene expression along with cell survival. Together, our findings reveal DPF2 as a bona fide H3K14la effector that couples histone lactylation to gene transcription and cell survival, offering insight into how histone Kla engages in transcription and tumorigenesis.
赖氨酸乳酰化（Kla）是一种新型的组蛋白修饰，参与转录等多种功能过程的调控。然而，由于对其识别蛋白缺乏了解，这种组蛋白修饰在癌症中的作用机制仍未得到探索。在这里，我们观察到宫颈癌（CC）细胞经历代谢重编程，导致乳酸积累，从而促进组蛋白乳酰化，特别是H3K14la。利用多价光亲和探针结合定量蛋白质组学方法，我们确定DPF2为H3K14la的候选靶点。生化研究以及CUT&Tag分析表明，DPF2能够与H3K14la结合，并与其在致癌基因启动子上共定位。值得注意的是，通过结构导向突变破坏DPF2-H3K14la相互作用会减弱那些与癌症相关的基因表达以及细胞存活。总之，我们的研究结果揭示DPF2是一种真正的H3K14la效应因子，它将组蛋白乳酰化与基因转录和细胞存活联系起来，为组蛋白Kla如何参与转录和肿瘤发生提供了见解。
