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Supplementary Data from Long-Chain Acyl-CoA Synthetase 4–Mediated Fatty Acid Metabolism Sustains Androgen Receptor Pathway–Independent Prostate Cancer

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posted on 2023-04-03, 19:40 authored by Yongjie Ma, Xiaohan Zhang, Omar Awad Alsaidan, Xiangkun Yang, Essilvo Sulejmani, Junyi Zha, Zanna Beharry, Hanwen Huang, Michael Bartlett, Zachary Lewis, Houjian Cai

Table S1. ChIP-qPCR primer sequences 5 kb upstream of ACSL4 Table S2. Primer sequences used for shRNAs, RT-PCR and ACSL4 primers 9 Figure S1. ACSLs expression levels in prostate cancer cell lines. Figure S2, related to Figure 3. Identification of AR binding sites in the promoter region of ACSL4 by ChIP-qPCR. Figure S3. ACSL3 and 4 regulation of the biosynthesis of fatty acyl-CoAs and catalytic efficiency. Figure S4. Verification of Myr-Src antibody. wn of ACSL3 has no effect on global protein myristoylation or myristoylSrc in PC-3 and DU14. Figure S5. Knockdown of ACSL3 has no effect on global protein myristoylation or myristoylSrc in PC-3 and DU145 cells. Figure S6, related to Figure 5. Knockdown of ACSL4 regulates the cell cycle in PC-3 and DU145 cells.

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ARTICLE ABSTRACT

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. AR coordinately regulates the expression of ACSL3 and ACSL4, such that AR pathway–independent prostate tumors become dependent on ACSL4-mediated fatty acid metabolism.

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