CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

Abstract

Background Resistance to androgen deprivation therapy remains a major challenge for the clinical treatment of patients with castration-resistant prostate cancer (CRPC). CYP1B1, a critical enzyme that catalyzes the conversion of estradiol to 4-Hydroxy-17β-estradiol (4-OHE2), has been reported to promote the development and progression of hormone-related cancer, but its role in CRPC is unclear. Methods To explore the underlying mechanism which CYP1B1 promotes the prostate cancer stem cells (PCSCs) characteristics, bioinformatics analyses of human clinical prostate cancer (PCa) datasets were performed. CYP1B1, IL6, and estrogen receptor-α (ERα) expression levels were evaluated in PCa and CRPC tissues via immunohistochemistry. The high-performance liquid chromatography-mass spectrometry assay was carried out to examine intracellular 4-OHE2 levels. Serum-free suspension culture and flow cytometry assays were performed to evaluate PCSCs. Chromatin immunoprecipitation was used to validate that 4-OHE2 recruited ERα to the IL6 promoter. Results CYP1B1 expression was significantly increased in CRPC tissues and androgen-independent PCa cell lines. CYP1B1+ PCa cells were significantly enriched in bicalutamide-treated LNCaP cells, and CYP1B1 knockdown reduced the cell viability under bicalutamide treatment. In addition, CYP1B1 knockdown decreased the intracellular 4-OHE2 concentration, accompanied by reduced PCSC characteristics. In PCa cells, 4-OHE2 stimulated ERα transcriptional activity and upregulated the expression of IL6 and downstream genes of the IL6-STAT3 signaling. 4-OHE2 increased cell viability under bicalutamide treatment and promoted PCSC characteristics, while IL6 neutralizing antibody reversed these effects. Mechanistically, siERα and the ER antagonist ICI182780 significantly attenuated 4-OHE2-induced IL6 expression, and 4-OHE2 promoted the binding of ERα to the estrogen response element of the IL6 promoter. Conclusions Our findings indicate that CYP1B1-catalyzed 4-OHE2 enhanced PCSC characteristics and attenuated bicalutamide sensitivity by ERα-mediated the IL6-STAT3 pathway activation. Our study further emphasizes the role of CYP1B1 in castration resistance and illustrates a novel mechanism of CRPC development. Graphical Abstract

SFRP1 induces a stem cell phenotype in prostate cancer cells

“…In addition, we confirmed that cells treated with SFRP1 showed increased clonogenic potential. This is also consistent with other studies assessing the clonogenic potential and drug resistance of prostate cancer stem cells ( Todaro et al, 2007 ; Rajendran & Jain, 2018 ; Lin et al, 2022 ). It has been reported that SFRP1 is downregulated in epithelial lines of prostate cancer by a mechanism that involves DNA hypermethylation and an increase in H3K27me3 signal in histones ( García-tobilla et al, 2016 ).…”

CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers

“…ssGESA analysis CYP1B1 was associated with melatonergic and immune-related pathways and therapeutic response. Recent studies showed that CYP1B1 was involved in the drug resistance of tumor cells, such as paclitaxel and docetaxel [ 45 , 46 , 47 ]. The clinical trial of CYP1B1-directed vaccination identified that patients with solid and hematologic tumors can benefit from anti-CYP1B1 immunity [ 48 ].…”

CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer

“…This mechanism may explain how CYP1B1 protects tumor cells from ferroptosis. Recently, researchers have that CYP1B1 plays a critical role in anti-cancer drug resistance [23][24][25][26]. Additionally, the role of CYP1B1 is also described in tumor proliferation and metastasis [27,28].…”