Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China.
Theranostics. 2021 Jan 1;11(2):841-860. doi: 10.7150/thno.49384. eCollection 2021.
Current endocrine therapy for prostate cancer (PCa) mainly inhibits androgen/androgen receptor (AR) signaling. However, due to increased intratumoural androgen synthesis and AR variation, PCa progresses to castration-resistant prostate cancer (CRPC), which ultimately becomes resistant to endocrine therapy. A search for new therapeutic perspectives is urgently needed. By screening lipid metabolism-related gene sets and bioinformatics analysis in prostate cancer database, we identified the key lipid metabolism-related genes in PCa. Bisulfite genomic Sequence Polymerase Chain Reaction (PCR) (BSP) and Methylation-Specific Polymerase Chain Reaction (PCR) (MSP) were preformed to detect the promoter methylation of ACSS3. Gene expression was analyzed by qRT-PCR, Western blotting, IHC and co-IP. The function of ACSS3 in PCa was measured by CCK-8, Transwell assays. LC/MS, Oil Red O assays and TG and cholesterol measurement assays were to detect the levels of TG and cholesterol in cells. Resistance to Enzalutamide in C4-2 ENZR cells was examined in a xenograft tumorigenesis model in vivo. We found that acyl-CoA synthetase short chain family member 3 (ACSS3) was downregulated and predicted a poor prognosis in PCa. Loss of ACSS3 expression was due to gene promoter methylation. Restoration of ACSS3 expression in PCa cells significantly reduced LD deposits, thus promoting apoptosis by increasing endoplasmic reticulum (ER) stress, and decreasing de novo intratumoral androgen synthesis, inhibiting CRPC progression and reversing Enzalutamide resistance. Mechanistic investigations demonstrated that ACSS3 reduced LD deposits by regulating the stability of the LD coat protein perilipin 3 (PLIN3). Our study demonstrated that ACSS3 represses prostate cancer progression through downregulating lipid droplet-associated protein PLIN3.
目前，用于前列腺癌（PCa）的内分泌治疗主要抑制雄激素/雄激素受体（AR）信号。然而，由于肿瘤内雄激素合成增加和 AR 变异，PCa 进展为去势抵抗性前列腺癌（CRPC），最终对内分泌治疗产生耐药性。迫切需要寻找新的治疗视角。 通过在前列腺癌数据库中筛选脂质代谢相关基因集和生物信息学分析，我们确定了 PCa 中关键的脂质代谢相关基因。亚硫酸氢盐基因组序列聚合酶链反应（PCR）（BSP）和甲基化特异性聚合酶链反应（PCR）（MSP）用于检测 ACSS3 的启动子甲基化。通过 qRT-PCR、Western blotting、IHC 和 co-IP 分析基因表达。通过 CCK-8、Transwell 测定、LC/MS、油红 O 测定和 TG 和胆固醇测定测定来检测细胞内 TG 和胆固醇的水平。在体内异种移植肿瘤发生模型中检查 ACSS3 对恩杂鲁胺的耐药性。 我们发现酰基辅酶 A 合成酶短链家族成员 3（ACSS3）在 PCa 中下调并预测预后不良。ACSS3 表达的丧失是由于基因启动子甲基化。在 PCa 细胞中恢复 ACSS3 表达可显著减少 LD 沉积物，从而通过增加内质网（ER）应激促进细胞凋亡，并减少新合成的肿瘤内雄激素，抑制 CRPC 进展并逆转恩杂鲁胺耐药性。机制研究表明，ACSS3 通过调节 LD 外壳蛋白 perilipin 3（PLIN3）的稳定性来减少 LD 沉积物。 我们的研究表明，ACSS3 通过下调与脂滴相关的蛋白 perilipin 3（PLIN3）来抑制前列腺癌的进展。
