Reversing enhancer RNA–mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models
Xiang Li, Rui Sun, Hao Li, Jacob J. Orme, Xu Zhang, Yu Hou, Sean S. Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang
Xiang Li, Rui Sun, Hao Li, Jacob J. Orme, Xu Zhang, Yu Hou, Sean S. Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang
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Research Article Immunology Oncology

Reversing enhancer RNA–mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models

Abstract

Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKE eRNA, or IKBKE-e). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically “cold” cancers such as prostate cancer.

Authors

Xiang Li, Rui Sun, Hao Li, Jacob J. Orme, Xu Zhang, Yu Hou, Sean S. Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang

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Figure 5

Restored IKKε expression by AR-targeted therapy enables IFN signaling in IR cotreated prostate cancer cells.

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Restored IKKε expression by AR-targeted therapy enables IFN signaling in...
(A) Western blot analysis of the indicated proteins in C4-2, LNCaP, and Myc-CaP cells treated with vehicle or ENZ (10 μM, 48 hours) and then treated with or without IR (6 Gy). (B) Western blot analysis of the indicated proteins in C4-2, LNCaP, and Myc-CaP cells treated with CSS medium for 3 days and supplemented with vehicle or DHT (10 nM, 24 hours), and then treated with or without IR (6 Gy). (C) Western blot analysis of the indicated proteins in C4-2, LNCaP, and Myc-CaP cells treated with or without ARV110 (5 μM, 24 hours) followed by IR (6 Gy). (D–G) RT-qPCR analysis of ISG15 and IFIT1 mRNA expression in C4-2 (D and E) and Myc-CaP (F and G) cells treated with or without ARV110 (5 μM) and followed with or without IR (6 Gy). (H) Western blot analysis of the indicated proteins in C4-2 and LNCaP cells transfected with shNT or shIKBKE, then treated with or without ENZ (10 μM) and followed with or without IR (6 Gy). (I) Western blot analysis of the indicated proteins from C4-2 and LNCaP cells transfected with shNT or shIKBKE cultured in CSS medium supplemented with DHT (10 nM, 24 hours) and/or IR (6 Gy). (J) Western blot analysis of the indicated proteins from C4-2 cells transfected with a nonspecific (NS) control ASO or IKBKE-e–specific ASOs followed with or without IR (6 Gy). Data are displayed as the mean ± SD of triplicate experiments (D–G). Significance was determined by 1-way ANOVA, and Tukey’s correction was applied for multiple comparisons (D–G).