Super-enhancers (SEs) exerted a crucial role in regulating the transcription of oncogenes across various malignancies while the roles of SEs driven genes and the core regulatory elements remain elusive in LUAD. In this study, cancer-specific-SE-genes of lung adenocarcinoma (LUAD) were profiled through H3K27ac ChIP-seq data of cancer cell lines and normal lung tissues, which enriched in in biological processes and pathways integral to the pathophysiology of LUAD. Based on this study, LUAD cells were susceptible to SEs inhibitors, with a reduction of cell proliferation as well as an elevation of apoptosis upon JQ1 or THZ1 intervention. Moreover, the integration of SEs landscapes, CRISPRi, ChIP-PCR, Hi-C data analysis and dual-luciferase reporter assays revealed that myeloma overexpressed gene () was aberrantly overexpressed in LUAD via transcriptional activation by the core SE elements. Functionally, the knockdown of undermined cell proliferation in vitro and tumor growth in vivo. In addition, the knockdown of generated a prominent ferroptotic phenotype, characterized by elevation of intracellular ferrous iron, reactive oxygen species and lipid peroxidation, together with alteration in marker proteins (, , , and ). Instead, the overexpression of accelerated cell proliferation and abrogated ferroptosis. Clinically, the overexpression of was observed in LUAD tissues indicating a poor prognosis in patients with LUAD. Mechanistically, induced autophagic degradation of assumed a crucial role in the process of ferroptosis triggered by knockdown. Serving as an oncogene repressing ferroptosis, promoting proliferation as well as shortening survival in LUAD, SEs-mediated activation of might distinguish as a promising therapeutic target.

中文翻译：

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超级增强子介导的 MYEOV 上调抑制肺腺癌中的铁死亡

超级增强子 (SE) 在调节各种恶性肿瘤的癌基因转录中发挥着至关重要的作用，而 SE 驱动基因和核心调控元件的作用在 LUAD 中仍然难以捉摸。在这项研究中，通过癌细胞系和正常肺组织的 H3K27ac ChIP-seq 数据对肺腺癌 (LUAD) 的癌症特异性 SE 基因进行了分析，这些数据丰富了 LUAD 病理生理学不可或缺的生物过程和途径。根据这项研究，LUAD 细胞对 SE 抑制剂敏感，JQ1 或 THZ1 干预后细胞增殖减少，细胞凋亡增加。此外，SEs 景观、CRISPRi、ChIP-PCR、Hi-C 数据分析和双荧光素酶报告基因分析的整合表明，骨髓瘤过表达基因 () 通过核心 SE 元件的转录激活在 LUAD 中异常过表达。从功能上讲，抑制体外细胞增殖和体内肿瘤生长。此外，敲低产生了显着的铁死亡表型，其特征是细胞内亚铁、活性氧和脂质过氧化的升高，以及标记蛋白的改变（、、、和）。相反，过度表达会加速细胞增殖并消除铁死亡。临床上，在 LUAD 组织中观察到 的过度表达，表明 LUAD 患者预后不良。从机制上讲，诱导自噬降解在敲低引发的铁死亡过程中发挥着至关重要的作用。作为抑制铁死亡、促进增殖以及缩短 LUAD 生存期的癌基因，SE 介导的激活可能会成为一个有前途的治疗靶点。