Long-Chain Acyl-CoA Synthetase 4-Mediated Fatty Acid Metabolism Sustains Androgen Receptor Pathway-Independent Prostate Cancer.
Long-Chain Acyl-CoA Synthetase 4-Mediated Fatty Acid Metabolism Sustains Androgen Receptor Pathway-Independent Prostate Cancer.
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DOI：
10.1158/1541-7786.mcr-20-0379
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Cai H
中科院分区：
文献类型：
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作者：
Ma Y;Zhang X;Alsaidan OA;Yang X;Sulejmani E;Zha J;Beharry Z;Huang H;Bartlett M;Lewis Z;Cai H
雄激素剥夺治疗导致雄激素受体（AR）途径非依赖性前列腺癌伴脂肪酸代谢失调的病例增加。然而，目前尚不清楚前列腺癌细胞如何维持失调的脂肪酸代谢来驱动AR非依赖性前列腺癌。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ACSL 3和4的表达水平在前列腺癌细胞中受到雄激素AR信号的相反调节。AR作为转录抑制因子结合在ACSL 4启动子区，抑制其转录。雄激素-AR信号传导的抑制显著下调ACSL 3和PSA，但升高ACSL 4水平。ACSL 4调节广泛的脂肪酰辅酶A水平，其在脂肪酰辅酶A生物合成中的催化效率比ACSL 3高约1.9-4.3倍。此外，与ACSL 3相反，ACSL 4显着调节前列腺癌细胞中整体蛋白质肉豆蔻酰化或Src激酶的肉豆蔻酰化。ACSL 4的敲低抑制AR非依赖性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ACSL 4水平的激增增加了脂肪酰辅酶A的生物合成和蛋白豆蔻酰化，这表明当靶向雄激素AR信号传导时，ACSL 3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ACSL 4作为治疗AR非依赖性前列腺癌的潜在治疗靶点的机制。
Androgen deprivation therapy has led to elevated cases of androgen receptor (AR) pathway-independent prostate cancer with dys-regulated fatty acid metabolism. However, it is unclear how prostate cancer cells sustain dys-regulated fatty acid metabolism to drive AR-independent prostate cancer. Long-chain acyl-CoA synthetases (ACSLs) 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 1.9-4.3-fold higher than ACSL3. Additionally, 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.