Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan.
Nat Commun. 2021 Apr 23;12(1):2398. doi: 10.1038/s41467-021-22652-9.
Arginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.
精氨酸在细胞生理学中发挥着多种作用。作为一种半必需氨基酸，精氨酸缺乏已被用于靶向具有精氨酸合成缺陷的癌症。缺乏精氨酸的癌细胞表现出线粒体功能障碍、转录重编程，最终导致细胞死亡。在本研究中，我们在前列腺癌细胞中表明，精氨酸作为一种表观遗传调节剂，调节组蛋白乙酰化，导致核编码氧化磷酸化（OXPHOS）基因的全局上调。精氨酸将 TEAD4 保留在核内，增强其募集到 OXPHOS 基因的启动子/增强子区域，并以 YAP1 非依赖性但 mTOR 依赖性的方式介导协调上调。精氨酸还激活赖氨酸乙酰转移酶的表达，并增加组蛋白乙酰化和乙酰辅酶 A 的整体水平，促进 TEAD4 募集。沉默 TEAD4 可抑制 OXPHOS 功能和前列腺癌细胞在体外和体内的生长。鉴于 TEAD4 表达与前列腺癌发生之间的强相关性，靶向 TEAD4 可能有助于增强精氨酸剥夺治疗和前列腺癌治疗。
