The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma

Abstract

Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis.

The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

“…In keratinocytes, RIPK4 and IRF6 function as a cell-intrinsic signaling axis that not only regulates keratinocyte differentiation but also mediates the expression of proinflammatory cytokines such as CCL5 and CXCL11 (Kwa et al 2016 ). In addition, studies suggest that RIPK4, acting through IRF6, may regulate ELOVL4 to control lipid and fatty acid metabolism (Oberbeck et al 2019 ; Yan et al 2023 ). Botti et al reported a tumor-suppressive function of IRF6 in squamous cell carcinomas (Botti et al 2011 ); however, studies on melanoma are limited.…”

Identification and Validation of a Cancer-Testis Antigen-Related Signature to Predict the Prognosis in Stomach Adenocarcinoma

“…ELOVL4, a newly identified CTAs-related gene, has been explored in several tumours, including neuroblastoma 33 , squamous cell carcinoma 34 , bladder cancer 35 , glioblastoma multiforme (GBM) 36 . Based on our in vitro experiments, we found that siRNA-mediated inhibition of ELOVL4 suppressed the proliferation of HCG-27 and AGS cells, as confirmed by CCK-8, colony formation, and EdU assays.…”

A novel telomere-related genes model for predicting prognosis and treatment responsiveness in diffuse large B-cell lymphoma

“…As for ELOVL4, the effects in tumors remain controversial. It has been reported that ELOVL4 serves as a tumor suppressor via the NOTCH-RIPK4-IRF6-ELOVL4 axis in squamous cell carcinoma, and its overexpression is related to the good prognosis for neuroblastoma patients [ 33 , 34 ]. On the contrary, ELOVL4 is identified as a risk gene in gastric cancer [ 35 ].…”