Androgen deprivation therapy has led to elevated cases of androgen receptor (AR) pathway–independent prostate cancer with dysregulated fatty acid metabolism. However, it is unclear how prostate cancer cells sustain dysregulated fatty acid metabolism to drive AR-independent prostate cancer. Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of fatty acids into fatty acyl-CoAs that are required for fatty acid metabolism. In this study, we demonstrate that expression levels of ACSL3 and 4 were oppositely regulated by androgen–AR signaling in prostate cancer cells. AR served as a transcription suppressor to bind at the ACSL4 promoter region and inhibited its transcription. Inhibition of androgen–AR signaling significantly downregulated ACSL3 and PSA, but elevated ACSL4 levels. ACSL4 regulated a broad spectrum of fatty acyl-CoA levels, and its catalytic efficiency in fatty acyl-CoAs biosynthesis was about 1.9- to 4.3-fold higher than ACSL3. In addition, in contrast to ACSL3, ACSL4 significantly regulated global protein myristoylation or myristoylation of Src kinase in prostate cancer cells. Knockdown of ACSL4 inhibited the proliferation, migration, invasion, and xenograft growth of AR-independent prostate cancer cells. Our results suggest that the surge of ACSL4 levels by targeting AR signaling increases fatty acyl-CoAs biosynthesis and protein myristoylation, indicating the opposite, yet complementary or Yin-Yang regulation of ACSL3 and 4 levels in sustaining fatty acid metabolism when targeting androgen–AR signaling. This study reveals a mechanistic understanding of ACSL4 as a potential therapeutic target for treatment of AR-independent prostate cancer. Implications: AR coordinately regulates the expression of ACSL3 and ACSL4, such that AR pathway–independent prostate tumors become dependent on ACSL4-mediated fatty acid metabolism.

中文翻译：

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长链酰基辅酶A合成酶4介导的脂肪酸代谢维持雄激素受体途径非依赖性前列腺癌

雄激素剥夺疗法导致雄激素受体 (AR) 通路非依赖性前列腺癌病例增加，伴有脂肪酸代谢失调。然而，尚不清楚前列腺癌细胞如何维持失调的脂肪酸代谢以驱动不依赖 AR 的前列腺癌。长链酰基辅酶A合成酶（ACSL）催化脂肪酸转化为脂肪酸代谢所需的脂肪酰基辅酶A。在这项研究中，我们证明了 ACSL3 和 4 的表达水平受到前列腺癌细胞中雄激素-AR 信号传导的相反调节。AR 作为转录抑制因子与 ACSL4 启动子区域结合并抑制其转录。抑制雄激素-AR 信号显着下调 ACSL3 和 PSA，但升高 ACSL4 水平。ACSL4 调节广泛的脂肪酰基辅酶 A 水平，其在脂肪酰基辅酶A生物合成中的催化效率比ACSL3高约1.9至4.3倍。此外，与 ACSL3 相比，ACSL4 显着调节前列腺癌细胞中 Src 激酶的全局蛋白肉豆蔻酰化或肉豆蔻酰化。ACSL4 的敲低抑制了不依赖 AR 的前列腺癌细胞的增殖、迁移、侵袭和异种移植物生长。我们的研究结果表明，通过靶向 AR 信号传导的 ACSL4 水平激增增加了脂肪酰基辅酶 A 的生物合成和蛋白质肉豆蔻酰化，表明当靶向雄激素-AR 信号传导时，ACSL3 和 4 水平在维持脂肪酸代谢中的相反但互补或阴阳调节. 这项研究揭示了对 ACSL4 作为治疗 AR 非依赖性前列腺癌的潜在治疗靶点的机制理解。影响：