Reactivation of androgen receptor-regulated lipid biosynthesis drives the progression of castration-resistant prostate cancer

Abstract

Androgen receptor (AR) is a transcriptional activator that in prostate cells stimulates gene expression required for various cellular functions, including metabolisms and proliferation. AR signaling is also essential for the development of hormone-dependent prostate cancer (PCa) and its activity can be blocked by androgen deprivation therapies (ADTs). Although PCa patients initially respond well to ADTs, the cancer inevitably relapses and progresses to lethal castration-resistant prostate cancer (CRPC). Although AR activity is generally restored in CRPC despite the castrate level of androgens, it is unclear whether AR signaling is significantly reprogrammed. In this study, we examined the AR cistrome in a PCa cell line-derived CRPC models using integrated bioinformatical analyses. Significantly, we found that the AR cistrome is largely retained in the CRPC stage. In particular, AR-mediated lipid biosynthesis is highly conserved and reactivated during the progression to CRPC, and increased level of lipid synthesis is associated with poor prognosis. The restoration of lipid biosynthetic pathways is partially due to the increased expression of AR splice variants. Blocking lipid/cholesterol synthesis in AR variants-expressing CRPC cell line and xenograft models markedly reduces tumor growth through inhibition of mTOR pathway. Silencing the expression of a fatty acid elongase, ELOVL7, also leads to the regression of CRPC xenograft tumors. These results demonstrate the importance of reactivation of AR-regulated lipid biosynthetic pathways in driving CRPC progression, and suggest that ADTs may be therapeutically enhanced by blocking lipid biosynthetic pathways.

Lipogenic effects of androgen signaling in normal and malignant prostate

“…In view of the relationship between androgens and lipid metabolism, several studies have reported that genes mediating the lipogenesis pathway ( i.e. FASN , SREBP1 ) that were initially suppressed following castration were subsequently up-regulated or re-activated during the emergence of CRPC [ 70 , 118 , 124 ]. Indeed, AR-mediated lipogenesis is a highly-conserved metabolic feature of CRPC ( Fig.…”

“…Indeed, AR-mediated lipogenesis is a highly-conserved metabolic feature of CRPC ( Fig. 1 ), suggesting the potential of lipid metabolism as a key survival pathway that promotes resistance [ 124 ].…”

“…Notably, a combination of simvastin and enzalutamide significantly inhibited the growth of enzalutamide-resistant PCa cells in vitro and in vivo [ 125 ]. Another study demonstrated that silencing the expression of ELOVL7 (a fatty acid elongase enzyme) reduced growth of CRPC xenograft tumours in mice [ 124 ]. Furthermore, Flaig et al.…”

Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC)

“…Increasing evidence shows that the lethal PCa is associated with deregulation of lipid or cholesterol biosynthesis (20 -23) and that lipid biosynthesis induced by AR reactivation can induce resistance to androgen-deprivation therapy and contributes to CRPC progression (24). For enzalutamide resistance, cholesterol is capable of participating in intracrine androgen biosynthesis, conferring PCa cells with resistance to enzalutamide (7).…”

The Signaling Pathways Project: an integrated ‘omics knowledgebase for mammalian cellular signaling pathways

“…MBOAT2 has rankings in both the AR-Hs-All TC (CPV = 3.7E-38, 99.96 th percentile) and ChIP-Seq (99 th percentile) consensomes comparable to those of canonical AR target genes such as KLK3 and TMPRSS2. In contrast to the large volume of literature devoted to these targets however, with the exception of a mention in a couple of androgen expression profiling studies 13,14 , the functional role of MBOAT2 in the context of AR signaling has been entirely unstudied. In validation of its elevated AR consensome ranking, we confirmed that MBOAT2 was an ARregulated gene in cultured prostate cancer cell lines (Fig.…”