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

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.

Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer

“…General strategies in bioinformatically analyzing KDM5B mRNA expression and correlation with patient survival have been described in our recent publications [35,36]. Briefly, KDM5B mRNA levels in normal human tissues (Supplementary Figure 1A) were extracted from the GTEx (Genotype-Tissue Expression) data portal (https://gtexportal.org/).…”

“…Basic procedures for these experiments have been previously described [35,36,[49][50][51][52]. After sacrificing mice at the age of 3 months, the prostates were surgically removed along with the urogenital tract.…”

“…Indeed, epigenetic events, mediated by histonemodifying enzymes, may be intimately involved in regulating AR signaling and PCa heterogeneity [27,37,38]. Our recent studies [35,36] indicate that not only the expression of AR, but its transcriptional activity (as judged by the expression levels of AR transcriptional targets such as LRIG1) is also highly heterogeneous contributing to intratumor cellular heterogeneity in PCa.…”

“…Of note, KDM5B induces CTH and mediates therapeutic resistance in breast cancer [22]. As PCa is also a hormone-driven, luminaltype cancer with significant cellular heterogeneity and CTH [35,36], KDM5B might play similar functions in PCa. Indeed, epigenetic events, mediated by histonemodifying enzymes, may be intimately involved in regulating AR signaling and PCa heterogeneity [27,37,38].…”

LRIG1 regulates invasion and migration of human gliomas through SNAI2 and E-cadherin

“…has been identified as a tumor suppressor in human cancers, such as prostate cancer [2] , non-small cell lung cancer [3] , thyroid cancer [4] as well as gliomas [5] . The SNAI2 gene encoding Slug, an oncogenic transcriptional repressor acting as a key regulator of cell migration, has been found overexpressed in many cancers such as leukemia, lung cancer, esophageal cancer, colorectal cancer, prostate cancer, breast cancer and ovarian cancer [6] .…”