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 5

Src mediates the UGT2B17 functions in regulating gene transcription.

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Src mediates the UGT2B17 functions in regulating gene transcription. (A)...
(A) RNA-Seq analysis of LN95(KO) cells transfected with control, Src(Y530F), or Src(K259M) (n = 2 repeats). GSEA tested the association between gene sets altered by Src(Y530F) or Src(K259M) and gene sets altered by UGT2B17 knockout in LNCaP95 cells. (B) Coomassie staining of purified UGT2B17 and Src proteins was shown on an SDS gel. Purified Flag-UGT2B17 and His-Src were used to perform co-IP assays using Flag and His tag antibodies, respectively. (C) Co-IP of HA-tagged full-length and deletion mutants of Src with Flag-tag UGT2B17, followed by immunoblotting with the indicated antibodies. (D) Co-IP of Flag-tag full-length and deletion mutants of UGT2B17 with HA-tagged Src. Immunoblotting assays were performed with the indicated antibodies. (E) Co-IP of Flag-tag UGT2B17 and UGTm with Flag or Src followed by immunoblotting analysis with the indicated antibodies. (F) LN95(KO) cells were transfected with control, UGT2B17, or UGTm, followed by treatments of control or 10 nM of dasatinib. Immunoblotting assays were conducted using antibodies against Src, pSrc(419), and Flag. (G) LN95(KO) cells were transfected with control, UGT2B17, or UGTm. Co-IP of Flag-tag UGT2B17 and UGTm with PTPN1 and Src followed by immunoblotting analysis with the indicated antibodies. (H) LN95(KO) cells were transfected with UGT2B17 or UGTm in the presence of control or siRNA against PTPN1, followed by immunoblotting with antibodies against Flag, Src, pSrc(419), and PTPN1. (I) PLAs were performed on PCa tissue microarrays containing tissue cores from benign prostate, primary PCa, and CRPC samples using UGT2B17 and Src antibodies. Pathology scoring of UGT2B17-Src protein interactions was plotted. (J) PLAs were performed on PCa tissue microarrays containing PCa tissue cores from tumors treated with various duration of neoadjuvant hormone therapy. Pathology scoring of UGT2B17-Src protein interactions was plotted. Experiments in B–H were performed 3 times with similar results obtained. Data are shown as the mean ± SEM. Statistics performed by 1-way ANOVA test. ***P < 0.001.