LRIG1 is a Pleiotropic Androgen Receptor-Regulated Feedback Tumor Suppressor in Prostate Cancer

LRIG1 has been reported to be a tumor suppressor in gastrointestinal tract and epidermis. However, little is known about the expression, regulation and biological functions of LRIG1 in prostate cancer (PCa). We find that LRIG1 isoverexpressed in PCa, but its expression correlates with better patient survival. Functional studies reveal strong tumor-suppressive functions of LRIG1 in both AR⁺ and AR⁻ xenograft models, and transgenic expression of LRIG1 inhibits tumor development in Hi-Myc and TRAMP models. LRIG1 also inhibits castration-resistant PCa and exhibits therapeutic efficacy in pre-established tumors. We further show that 1) AR directly transactivates LRIG1 through binding to several AR-binding sites in LRIG1 locus, and 2) LRIG1 dampens ERBB expression in a cell type-dependent manner and inhibits ERBB2-driven tumor growth. Collectively, our study indicates that LRIG1 represents a pleiotropic AR-regulated feedback tumor suppressor that functions to restrict oncogenic signaling from AR, Myc, ERBBs, and, likely, other oncogenic drivers.

Authors: Qiuhui Li, Bigang Liu, Hsueh-Ping Chao, Yibing Ji, Yue Lu, Rashid Mehmood, Collene Jeter, Taiping Chen, John R. Moore, Wenqian Li, Can Liu, Kiera Rycaj, Amanda Tracz, Jason Kirk, Tammy Calhoun-Davis, Jie Xiong, Qu Deng, Jiaoti Huang, Barbara A. Foster, Abhiram Gokhale, Xin Chen & Dean G. Tang

Author information: These authors contributed equally: Qiuhui Li, Bigang Liu.
Affiliations:
1. Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA: Qiuhui Li, Yibing Ji, Rashid Mehmood, Kiera Rycaj, Amanda Tracz, Jason Kirk, Jie Xiong, Qu Deng, Barbara A. Foster, Abhiram Gokhale, Xin Chen & Dean G. Tang
2. State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education (KLOBM), School and Hospital of Stomatology, Wuhan University, 430079, Wuhan, China: Qiuhui Li
3. Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park, Smithville, TX, 78957, USA: Qiuhui Li, Bigang Liu, Hsueh-Ping Chao, Yue Lu, Collene Jeter, Taiping Chen, John R. Moore, Wenqian Li, Can Liu, Kiera Rycaj, Tammy Calhoun-Davis, Jie Xiong, Qu Deng, Xin Chen & Dean G. Tang
4. Department of Pathology, Duke University of School of Medicine, Durham, NC, 27710, USA: Jiaoti Huang
5. Department of Oncology, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology (HUST), 430030, Wuhan, China
Xin Chen
6. Cancer Stem Cell Institute, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, 200120, Shanghai, China: Dean G. Tang
Contributions
Q.L., B.L., X.C., and D.G.T. conceived the project, designed experiments, and interpreted the results. H.P.C., Y.J., C.J., and Y.L. participated in the design, execution, and interpretation of experiments related to bioinformatics analysis. Q.L., X.C., and B.L. performed most of the experiments presented herein with technical assistance from Y.J., R.M., T.C., J.R.M., W.L., C.L., K.R., J.K., J.X., A.G., and Q.D.; A.T., J.K., B.A.F., and T.C.D. helped with animal experiments. J.H. provided PCa TMA and whole-mount specimens and helped with data interpretation. Q.L., X.C., and D.T. wrote the manuscript. All authors read and approved the manuscript.

Article Citation: Li, Q., Liu, B., Chao, H. et al. LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer. Nat Commun 10, 5494 (2019) doi:10.1038/s41467-019-13532-4

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