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 2

UGT2B17 regulates UPR in PCa cells.

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UGT2B17 regulates UPR in PCa cells. (A) LNCaP cells transfected with Fla...
(A) LNCaP cells transfected with Flag-tagged control, UGT2B17, C1, or C2 constructs were subjected to co-IP with a Flag antibody, followed by MS analysis (n = 4 repeats/co-IP plus MS). Proteins bound to Flag-UGT2B17, Flag-C1, and Flag-C2, compared with Flag-control (with unique peptides > 3 and abundance > 100,000), were analyzed using Metascape. The top ranked gene annotations were ranked by –log10(q value) and plotted. (B) Selected proteins within the annotation groups from A are listed. (C) Co-IP of Flag-tagged UGT2B17 or UGTm with proteins identified from A. (D) LN95 and LN95(KO) cells were treated with increasing doses of TG and MG for 0–96 hours as indicated. Cell viability was measured by Incucyte and plotted over control at day 0. (E) A diagram summarizes 3 UPR pathways and their downstream effectors. (F) LNCaP95 and LN95(KO) cells were treated with increasing doses of TG for 24 hours, and mRNA levels of UPR genes were measured by real-time qPCR. (G) LNCaP95 and LN95(KO) cells were treated with increasing doses of TG for 24 hours, and protein levels of PERK and EIF2a and their phosphorylated forms were measured by immunoblotting. Densitometry of protein bands were quantified by ImageJ and normalized to that from vehicle treatment conditions. Experiments in C, D, F, and G were performed 3 times with similar results obtained. Data are shown as the mean ± SEM. Statistical tests performed by 2-way ANOVA test. *P < 0.05, **P < 0.01, ***P < 0.001.