RIP140 increases APC expression and controls intestinal homeostasis and tumorigenesis

Abstract

Deregulation of the Wnt/APC/β-catenin signaling pathway is an important consequence of tumor suppressor APC dysfunction. Genetic and molecular data have established that disruption of this pathway contributes to the development of colorectal cancer. Here, we demonstrate that the transcriptional coregulator RIP140 regulates intestinal homeostasis and tumorigenesis. Using Rip140-null mice and mice overexpressing human RIP140, we found that RIP140 inhibited intestinal epithelial cell proliferation and apoptosis. Interestingly, following whole-body irradiation, mice lacking RIP140 exhibited improved regenerative capacity in the intestine, while mice overexpressing RIP140 displayed reduced recovery. Enhanced RIP140 expression strongly repressed human colon cancer cell proliferation in vitro and after grafting onto nude mice. Moreover, in murine tissues and human cancer cells, RIP140 stimulated APC transcription and inhibited β-catenin activation and target gene expression. Finally, RIP140 mRNA and RIP140 protein levels were decreased in human colon cancers compared with those in normal mucosal tissue, and low levels of RIP140 expression in adenocarcinomas from patients correlated with poor prognosis. Together, these results support a tumor suppressor role for RIP140 in colon cancer.

Downregulation of RIP140 in hepatocellular carcinoma promoted the growth and migration of the cancer cells

“…RIP140 might be an attractive target to sensitize tumor cells to retinoid-based differentiation therapy in the cancer stem cell model [35]. Moreover, RIP140 was reported to control the intestinal homeostasis and tumorigenesis through upregulation of APC [36], a negative regulator of Wnt/beta-catenin signaling, which was very consistent with our observation in this study though RIP140 negatively regulated beta-catenin/TCF signaling in colon cancer and HCC through different mechanism. These studies suggested that RIP140 might regulate the activity of beta-catenin/TCF signaling at different levels.…”

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

“…The Wnt pathway involves various feedback loops that balance the opposing processes of cell proliferation and differentiation. Studies indicate that, even in the presence of heterozygousactivating mutations downstream of the FRZ receptor, mutationdriven Wnt-signaling activation can be further enhanced in APC min/+ mice and cells (40)(41)(42)(43)(44)(45). Our results highlighted that SETD2 fine-tuned Wnt signaling to safeguard ISCs or progenitor cells in the intestine, whereas downregulation facilitated inherently more proliferative and progenitor traits in ISCs in the Apc-mutated background ( Figure 8E).…”

Involvement of receptor-interacting protein 140 in estrogen-mediated osteoclasts differentiation, apoptosis, and bone resorption

“…RIP140 could implicate in the control of energy expenditure, metabolism, cognition, mammary gland development, and intestinal homeostasis [21,22]. Furthermore, RIP140 was also involved in Fig.…”