The HeyL-Aromatase Axis Promotes Cancer Stem Cell Properties by Endogenous Estrogen-Induced Autophagy in Castration-Resistant Prostate Cancer

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.

Patterns of Structural Variation Define Prostate Cancer Across Disease States

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation reflects the genomic landscape of this disease. We comprehensively characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes in mCRPC. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.

Ferroptosis inducers for prostate cancer therapy

Lipid peroxidation-driven iron-dependent ferroptosis is a regulated cell death mechanism implicated in numerous disease, such as neurological diseases, kidney injury, ischemia, and tumors, including prostate cancer. The cellular mechanisms of ferrosptosis are strongly associated with iron, reactive oxygen species and aminoacid metabolic pathways. Several compounds, namely ferroptosis inducers, impact on these pathways and trigger ferroptosis by i) inhibiting Xc– transporter system, ii) impairing GPX4 functions and iii) oxidizing iron and polyunsaturated phospholipids. Preclinical studies showed that in combination with conventional anticancer drugs, ferroptosis inducers are effective in prostate cancer and in combating the progression towards the castration resistant disease. This review overviews the mechanisms implicated in ferroptosis and discusses the findings achieved in prostate cancer.

Biomarkers of Castrate Resistance in Prostate Cancer: Androgen Receptor Amplification and T877A Mutation Detection by Multiplex Droplet Digital PCR

Androgen Receptor (AR) alterations (amplification, point mutations, and splice variants) are master players in metastatic castration resistant prostate cancer (CRPC) progression and central therapeutic targets for patient management. Here, we have developed two multiplexed droplet digital PCR (ddPCR) assays to detect AR copy number (CN) and the key point mutation T877A. Overcoming challenges of determining gene amplification from liquid biopsies, these assays cross-validate each other to produce reliable AR amplification and mutation data from plasma cell free DNA (cfDNA) of advanced prostate cancer (PC) patients. Analyzing a mixed PC patient cohort consisting of CRPC and hormone sensitive prostate cancer (HSPC) patients showed that 19% (9/47) patients had AR CN amplification. As expected, only CRPC patients were positive for AR amplification, while interestingly the T877A mutation was identified in two patients still considered HSPC at the time. The ddPCR based analysis of AR alterations in cfDNA is highly economic, feasible, and informative to provide biomarker detection that may help to decide on the best follow-up therapy for CRPC patients.