TY - JOUR
T1 - LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer
AU - Li, Qiuhui
AU - Liu, Bigang
AU - Chao, Hsueh Ping
AU - Ji, Yibing
AU - Lu, Yue
AU - Mehmood, Rashid
AU - Jeter, Collene
AU - Chen, Taiping
AU - Moore, John R.
AU - Li, Wenqian
AU - Liu, Can
AU - Rycaj, Kiera
AU - Tracz, Amanda
AU - Kirk, Jason
AU - Calhoun-Davis, Tammy
AU - Xiong, Jie
AU - Deng, Qu
AU - Huang, Jiaoti
AU - Foster, Barbara A.
AU - Gokhale, Abhiram
AU - Chen, Xin
AU - Tang, Dean G.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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 is overexpressed 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.
AB - 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 is overexpressed 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.
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U2 - 10.1038/s41467-019-13532-4
DO - 10.1038/s41467-019-13532-4
M3 - Article
C2 - 31792211
AN - SCOPUS:85075955400
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5494
ER -