Noncanonical functions of UGT2B17 promote castration-resistant prostate cancer progression
Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia H.Y. Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong
Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia H.Y. Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong
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Research Article Clinical Research Oncology

Noncanonical functions of UGT2B17 promote castration-resistant prostate cancer progression

Abstract

Androgen deprivation therapy is the primary treatment for advanced prostate tumors. While initially effective, tumor progression to the therapy-resistant stage is inevitable. Paradoxically, UDP glucuronosyltransferase family 2 member B17 (UGT2B17), the key enzyme responsible for androgen catabolism in prostate tumor cells, is upregulated in therapy-resistant tumors, though its role in tumor progression remains unclear. Here, we demonstrate that UGT2B17 possesses multiple oncogenic functions independent of androgen catabolism. It modulates protein-folding pathways, allowing tumor cells to endure therapy-induced stress. UGT2B17 also regulates transcription associated with cell division and the DNA damage response, enabling unchecked cell proliferation. Targeting the newly identified UGT2B17 functions using a combination of inhibitors reduced tumor growth in therapy-resistant tumor models, highlighting a promising therapeutic strategy. Collectively, these findings reveal a mechanism by which prostate tumors exploit UGT2B17 to evade therapy and highlight its potential as a therapeutic target in advanced prostate cancer.

Authors

Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia H.Y. Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong

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Figure 4

UGT2B17 regulates transcription associated with mitosis and DDR.

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UGT2B17 regulates transcription associated with mitosis and DDR. (A and ...
(A and B) RNA-Seq analysis comparing the transcriptome between LNCaP95 and LN95(KO) cells (n = 2 repeats). GSEA showed top ranked signal pathways regulated by UGT2B17 knockout. (C) Real-time qPCR validated 8 DDR genes altered by UGT2B17 knockout in LNCaP95 cells. (D) LNCaP, LNCaP95, and LN95(KO) cells were treated with increasing doses of CPT. Indicated protein markers were measured by immunoblotting. Densitometry of protein bands from triplicate experiments was determined by ImageJ and plotted. (E) LN95(KO) cells were transfected with control, UGT2B17, or UGTm vector and subjected to RNA-Seq analysis. GSEA tested the association between the gene sets altered by UGT2B17 or UGTm and the gene sets altered by UGT2B17 knockout in the LNCaP95 cells. (F) A heatmap shows RNA-Seq data of genes associated with cell mitosis and DDR in LN95(KO) cells overexpressing either UGT2B17 or UGTm. (G) LNCaP95, LN95(KO), and LN95(KO) cells overexpressing UGT2B17 or UGTm vector were used to measure the number of p-H2AX foci in 5 randomly selected high-power fields. (H) LNCaP95, LN95(KO), and LN95(KO) cells overexpressing UGT2B17 or UGTm were used to measure the apoptosis marker of cPARP. Experiments in C, D, G, and H were performed 3 times with similar results obtained. Data are shown as the mean ± SEM. Statistical tests performed by 2-way ANOVA test (D), 1-way ANOVA test (G). *P < 0.05, **P < 0.01, ***P < 0.001.