RNF168 facilitates proliferation and invasion of esophageal carcinoma, possibly via stabilizing STAT1

Abstract

Oesophageal cancer ranks as one of the most common malignancy in China and worldwide. Although genome‐wide association studies and molecular biology studies aim to elucidate the driver molecules in oesophageal cancer progression, the detailed mechanisms remain to be identified. Interestingly, RNF168 (RING finger protein 168) shows a high frequency of gene amplification in oesophageal cancer from TCGA database. Here, we report an important function for RNF168 protein in supporting oesophageal cancer growth and invasion by stabilizing STAT1 protein. RNF168 gene is amplified in oesophageal cancer samples, which tends to correlate with poor prognosis. Depletion RNF168 causes decreased cell proliferation and invasion in oesophageal cancer cells. Through unbiased RNA sequencing in RNF168 depleted oesophageal cancer cell, we identifies JAK‐STAT pathway is dramatically decreased. Depletion RNF168 reduced JAK‐STAT target genes, such as IRF1, IRF9 and IFITM1. Immuno‐precipitation reveals that RNF168 associates with STAT1 in the nucleus, stabilizing STAT1 protein and inhibiting its poly‐ubiquitination and degradation. Our study provides a novel mechanism that RNF168 promoting JAK‐STAT signalling in supporting oesophageal cancer progression. It could be a promising strategy to target RNF168 for oesophageal cancer treatment.

A systematic and comprehensive analysis of colorectal squamous cell carcinoma: Implication for diagnosis and treatment

“…34,35 Overexpression of STAT1 was observed in many SCCs and can promote the malignant ability of SCC. [36][37][38] Our findings suggested that TP63 and STAT1 may play a critical role in CSCC, and more studies on their mechanisms are necessary for the future.…”

RNF168 suppresses the cancer stem cell‐like traits of nonsmall cell lung cancer cells by mediating RhoC ubiquitination

“…To firmly confirm this effect, we further detected the effects of RNF168 on the expression of CSC markers and tumor‐initiating ability of NSCLC cells and a consistent result was obtained; however, further cytometry analysis should be performed to isolate CSCs in NSCLC cells, which might be a better model to investigate the effects of RNF168 on lung CSC progression. As an E3 ubiquitin ligase, RNF168 has been shown to facilitate proliferation and invasion of esophageal carcinoma, and drive breast cancer proliferation, by stabilizing STAT1 or promoting estrogen receptor ɑ transcription, respectively 9,22 . Notably, a recent study indicated that RNF168 could restrain gastric cancer progression by inducing ubiquitination‐proteasome‐mediating degradation of RhoC protein, 17 which is regarded as a fascinating CSC therapeutic target 17 .…”

“…In addition to providing insights into cancer biology, there are also records showing that RNF168 is elevated in the immunohistochemical results of human clinical tumor specimens, which may affect the response to standard treatment and some emerging cancer‐targeted treatments 8 . Recent studies have shown that RNF168‐mediated ubiquitin signaling suppresses the viability of BRCA1‐null breast cancer, 7 while RNF168 was shown to facilitate the proliferation and invasion of esophageal carcinoma 9 . However, it is still lack of in‐depth research of RNF168 in lung cancer.…”

Multiomic Analysis of Methylation and Transcriptome Reveals a Novel Signature in Esophageal Cancer

“… 32 The dysregulation of the JAK/STAT signaling pathway has been implicated in the initiation and progression of various cancers, including EC. 33 - 35 Yu et al found that the JAK-STAT pathway was significantly reduced by unbiased RNA sequencing in RNF168-depleted EC cell. Silence of RNF168 reduces JAK-STAT target genes, such as IRF1, IRF9, and IFITM1.…”