Abstract
Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.
Highlights
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer mortality in men [1]
We examined the expression of Notch signaling downstream effectors in the The Cancer Genome Atlas (TCGA) and Oncomine databases and found that HeyL expression was significantly higher in PCa than in normal tissues (Figure 1A and Figures S2, S3)
HeyL expression was significantly upregulated in castration-resistant prostate cancer (CRPC) tissues compared to primary PCa tissues (Figure 1C), and HeyL expression was higher in the relapsed patient subset than in the nonrelapsed patient subset (Figure 1D)
Summary
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer mortality in men [1]. The effect of ADT is temporary, it eventually leads to lethal castration-resistant prostate cancer (CRPC) [3]. Based on the theory that the proliferation and survival of most PCa cells depend on the androgen signaling pathway, previous efforts have revealed the role of restored AR signaling (such as increased testosterone levels within the tumor), AR bypass signaling, and complete AR independence in CRPC [4,5,6]. On the other side of the coin, the upregulated expression and activity of estrogen receptor-a (ERa) and ERa‐regulated genes (e.g., MAPK, PI3K, the TMPRSS2‐ERG fusion, and NEAT1) during the progression of PCa to CRPC suggests that tumors can bypass the AR signaling axis by using estrogens for their growth [7,8,9]. Our previous studies have already shown that PCSCs exhibit higher ERa levels and that estradiol enhances their basal cell-like phenotype via the ERa-NOTCH1 axis, thereby promoting epithelial-mesenchymal transition [11]
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