LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer

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

doi:10.1038/s41467-019-13532-4

Abstract

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.

Highlights

134 kDa, the former of which could be cleaved into an N-ter ~110-kDa species and a C-ter 32-kDa species[4]
Upregulation of LRIG1 in prostate cancer (PCa) correlates with good survival
Among the 15 PCa datasets that had detectable LRIG1, LRIG1 mRNA was overexpressed in prostate tumors (T) compared to normal (N)/benign prostate tissues (Fig. 1a; Supplementary Figs. 2 and 3a)

Summary

Introduction

134 kDa, the former of which could be cleaved into an N-ter ~110-kDa species and a C-ter 32-kDa species[4] Associated with its inhibition of ERBB and other mitogenic signaling, LRIG1 has been evinced to play a critical role in regulating the quiescence and homeostasis of stem cells in the interfollicular epidermis[29,30,31,32] and the gastrointestinal (GI) tract including the small intestine, colon, and stomach[33,34,35,36,37,38]. Another concept derived from these studies is that LRIG1 expression marks stem/progenitor cells in these tissues. Our results demonstrate that LRIG1 represents an androgen receptor (AR) regulated gene and exhibits tumor-suppressive functions in both xenograft and genetic prostate tumor models

Methods

Results

Conclusion