Hepatocellular carcinoma (HCC) is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence. Clinical traits and RNA-seq of HCC patients in TCGA were used for weighted gene co-expression network analysis, where one module was significantly correlated with advanced pathological stage and stem cell population maintenance. Further analysis of this module by integrating data obtained from HCC patient nonresponders to tyrosine kinase inhibitors identified 361 commonly deregulated genes significantly enriched in the intracellular signal transduction pathway, with diacylglycerol kinase eta (DGKH) ranked as the most enriched gene in poorly differentiated HCC tumors. Clinically, DGKH was elevated in tumor tissues compared to non-tumor tissues. Patients with higher DGKH expression exhibited a more undifferentiated state and were less responsive to TKIs. Functional assays using DGKH-manipulated HCC cell lines demonstrated that DGKH augmented aggressive features, including cancer stemness, therapy resistance, and metastasis. Upstream of DGKH, we discovered that the E1A-associated protein p300 (EP300) binds to DGKH’s promoter region, thereby increasing its transcriptomic expression. Mechanistically, DGKH promotes mTOR signaling by producing phosphatidic acid (PA). In an immunocompetent mouse model, co-treatment with sorafenib and liver-directed AAV8-mediated Dgkh depletion significantly reduced tumor burden, self-renewal, PA production and mTOR signaling. Our research demonstrated that DGKH is a crucial oncometabolic regulator of cancer stemness and therapy resistance, inhibition of which may lead to more effective hepatocellular carcinoma treatment.

中文翻译：

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DGKH 介导的磷脂酸肿瘤代谢是肝细胞癌自我更新和治疗耐药的驱动因素


肝细胞癌 （HCC） 的特征是代谢途径异常，使癌细胞能够满足其能量需求并加速恶性进展。确定控制 HCC 治疗耐药性和自我更新的新型代谢参与者至关重要，因为这些特性可能是导致肿瘤复发的原因。采用 TCGA 中 HCC 患者的临床特征和 RNA-seq 进行加权基因共表达网络分析，其中 1 个模块与晚期病理分期和干细胞种群维持显著相关。通过整合从 HCC 患者对酪氨酸激酶抑制剂无反应者获得的数据，进一步分析了该模块，确定了 361 个通常失调的基因，这些基因在细胞内信号转导途径中显著富集，其中甘油二酯激酶 eta （DGKH） 被列为低分化 HCC 肿瘤中最富集的基因。临床上，与非肿瘤组织相比，肿瘤组织中的 DGKH 升高。DGKH 表达较高的患者表现出更未分化的状态，并且对 TKI 的反应较差。使用 DGKH 操纵的 HCC 细胞系的功能测定表明，DGKH 增强了侵袭性特征，包括癌症干性、治疗耐药性和转移。在 DGKH 的上游，我们发现 E1A 相关蛋白 p300 （EP300） 与 DGKH 的启动子区结合，从而增加其转录组表达。从机制上讲，DGKH 通过产生磷脂酸 （PA） 来促进 mTOR 信号转导。在免疫功能正常的小鼠模型中，与索拉非尼和肝脏定向 AAV8 介导的 Dgkh 耗竭共同治疗显着降低了肿瘤负荷、自我更新、PA 产生和 mTOR 信号传导。 我们的研究表明，DGKH 是癌症干性和治疗耐药性的重要肿瘤代谢调节因子，抑制其可能导致更有效的肝细胞癌治疗。