Centre Hospitalier Universitaire de Québec Research Center - Université Laval (CRCHUQc-UL), Faculty of Pharmacy and Centre de Recherche sur le Cancer, Université Laval, Québec, Canada.
CRCHUQc-UL and Faculty of Medicine-Université Laval, Québec, Canada.
Br J Cancer. 2023 Jan;128(2):285-296. doi: 10.1038/s41416-022-02040-w. Epub 2022 Nov 8.
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.
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.
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.
The distinctive and broad metabolic rewiring caused by UGT KO reinforces the need to examine their unique and divergent functions in PCa biology.
天然发生的种系基因缺失（KO）代表了一种独特的方法来探究基因功能。人类糖基转移酶 UGT2B17 和 UGT2B28 基因的完全缺失和差异表达与前列腺癌（PCa）风险和进展、白血病、自身免疫性疾病和其他疾病有关。
使用非靶向和靶向基于质谱的代谢组学分析方法，对精心匹配的、未经治疗的 PCa 病例进行分析，研究 UGT 缺乏的系统代谢后果。
每个 UGT KO 都会对 1545 种测量代谢物中的超过 5%产生不同影响，不同的代谢干扰影响相同的途径。一些被干扰的代谢物已知可促进 PCa 的生长、侵袭和转移，包括类固醇、神经酰胺和犬尿氨酸。在 UGT2B17 KO 中，失活的类固醇-葡糖苷酸的水平降低被硫酸化衍生物所补偿，后者构成了循环类固醇储库。UGT2B28 KO 表现出明显更低水平的氧化脂类物质，同时炎症介质减少，但在 PCa 细胞中作为酶的底物的神经酰胺增加。
UGT KO 引起的独特而广泛的代谢重排，加强了需要检查其在 PCa 生物学中独特和不同功能的必要性。
