Extensive metabolic consequences of human glycosyltransferase gene knockouts in prostate cancer.

Abstract

BACKGROUND:

Naturally occurring germline gene deletions (KO) represent a unique setting to interrogate gene functions. Complete deletions and differential expression of the human glycosyltransferase UGT2B17 and UGT2B28 genes are linked to prostate cancer (PCa) risk and progression, leukaemia, autoimmune and other diseases.

METHODS:

The systemic metabolic consequences of UGT deficiencies were examined using untargeted and targeted mass spectrometry-based metabolomics profiling of carefully matched, treatment-naive PCa cases.

RESULTS:

Each UGT KO differentially affected over 5% of the 1545 measured metabolites, with divergent metabolic perturbations influencing the same pathways. Several of the perturbed metabolites are known to promote PCa growth, invasion and metastasis, including steroids, ceramides and kynurenine. In UGT2B17 KO, reduced levels of inactive steroid-glucuronides were compensated by sulfated derivatives that constitute circulating steroid reservoirs. UGT2B28 KO presented remarkably lower levels of oxylipins paralleled by reduced inflammatory mediators, but higher ceramides unveiled as substrates of the enzyme in PCa cells.

CONCLUSION:

The distinctive and broad metabolic rewiring caused by UGT KO reinforces the need to examine their unique and divergent functions in PCa biology.

• Authors: Michèle Rouleau, Flora Nguyen Van Long, Véronique Turcotte, Patrick Caron, Louis Lacombe, Armen Aprikian, Fred Saad, Michel Carmel, Simone Chevalier, Eric Lévesque, Chantal Guillemette
• Journal: British journal of cancer (Br J Cancer) Vol. 128 Issue 2 Pg. 285-296 (01 2023) ISSN: 1532-1827 [Electronic] England
• PMID: 36347965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Glucuronides
• Steroids
• UGT2B17 protein, human
• UGT2B28 protein, human
• Glucuronosyltransferase

Topics

• Humans
• Male
• Gene Knockout Techniques
• Glucuronides
• Phenotype
• Prostatic Neoplasms (pathology)
• Steroids
• Glucuronosyltransferase (genetics)