CYP1B1 gene: Implications in glaucoma and cancer

Abstract

Glaucoma is a serious disease that can lead to irreversible loss of vision. Patients with primary congenital glaucoma may have elevated intraocular pressure. Hypertension causes damages to intraocular structures and affects the Schlemm's canal, collector channels, trabecular meshwork, and optic nerve's molecular structures. An important gene that is defective in patients with glaucoma is CYP1B1, a gene associated with optic nerve deterioration. CYP1B1is a key enzyme involved in the metabolism of exogenous and endogenous compounds. Also, it is critical in the detoxification of pre-carcinogens, such as polycyclic aromatic hydrocarbons and estrogen. It catalyzes their conversion into metabolites subsequently eliminated from the body. In malignant tumors, the CYP1B1 promoter is hypomethylated. CYP1B1 overexpression results in the conversion of estrogens to quinone forms, which bind with DNA and create a predisposition for cancer in several organs, such as the brain, breast, and ovary. Increased cytokine interleukin-6 and leptin lead to elevated CYP1B1 activity, which possibly causes cancer. In addition, the expression of aromatic hydrocarbon receptors is increased in tumor tissues, and it elevates oxidative stress and cell growth. TCGA database analysis showed increased survival at bladder and renal carcinoma when CYP1B1 expression is low. Therefore, alteration of CYP1B1 expression may suggest a therapeutic benefit for multiple diseases such as glaucoma and cancer.

Keywords: CYP1B1; Glaucoma; cancer; carcinogens; estrogens; optic nerve.

Figure 1

Human CYP1B1 located at 2p21-22 in the GLC3A critical region. The length of this gene is 8.5 kilobases, and it contains three exons and two introns: exon1 (371 bp), intron 1 (371 bp), exon 2 (1044 bp), intron 2 (3032 bp), and exon 3 (3707 bp). The open reading frame (ORF) starts from exon 2 and continues to exon 3. The ORF is translated into about 5.1 kb mRNA, which encodes a predicted 543 amino acids. Figure created by Biorender software.

Figure 2

CYP1B1 gene expression across diverse normal human tissues. The source of this figure is Genotype-Tissue expression (GTEx) project database, gtexportal.org.

Figure 3

Aromatic hydrocarbon in conjunction with CYP1B1 signalling pathway. A, Oestrogen binds with the oestrogen receptor alpha (ERa) to form an oestrogen-oestrogen receptor alpha complex (E-ERa), which induces an aromatic hydrocarbon receptor (AhR) gene. The AhR protein attaches to heat shock protein-90 (hsp90), XAP2 and P23 to form an AhR complex, then transport into the cell membrane. Also, AhR binds with a polycyclic aromatic hydrocarbon (PAH) ligand to form an AhR complex/PAH complex. The AhR complex dissociates to form a heterodimer, AhR-ligand/ARNT. The heterodimer with oestrogen promotes the CYP1B1 gene. The CYP1B1 enzyme is involved in oestrogen metabolism by converting oestrogen into 4-hydroxyestradiol, which depends on NADPH. The figure created by Biorender software. B, CYP1B1 gene involved in carcinogenesis pathway using Aromatic hydrocarbons leading to different types of cancers. The figure obtained from KEGG pathways database.

Figure 4

TCGA survival curves using Kaplan meier analysis. A, represents bladder urothelial carcinoma showing longer survival for low expression CYP1B1 patients. B, represents renal clear cell carcinoma showing extended survival for decreased expression CYP1B1 patients. Figures created from oncolnc.org website with TCGA database incorporated.

Figure 5

CYP1B1 protein-protein associations frpm STRING database. Colored nodes are query proteins and first shell of interactors. White nodes are second shell of interactors. filled nodes (structure inside the node) represent some 3D structure is known or predicted. Interactions include: i) known interactions from curated databases and experimentally determined, ii) predicted interactions by gene neighborhood, gene fusion, and gene co-occurrence, iii) others by text mining, co-expression, and protein homology. All interactions have been segregated by different colors.