The ubiquitin E3 ligase ARIH1 regulates hnRNP E1 protein stability, EMT and breast cancer progression

Abstract

The epithelial to mesenchymal transition (EMT), a process that is aberrantly activated in cancer and facilitates metastasis to distant organs, requires coordinated transcriptional and post-transcriptional control of gene expression. The tumor-suppressive RNA binding protein, hnRNP-E1, regulates splicing and translation of EMT-associated transcripts and it is thought that it plays a major role in the control of epithelial cell plasticity during cancer progression. We have utilized yeast 2 hybrid screening to identify novel hnRNP-E1 interactors that play a role in regulating hnRNP-E1; this approach led to the identification of the E3 ubiquitin ligase ARIH1. Here, we demonstrate that hnRNP-E1 protein stability is increased upon ARIH1 silencing, whereas, overexpression of ARIH1 leads to a reduction in hnRNP-E1. Reduced ubiquitination of hnRNP-E1 detected in ARIH1 knockdown (KD) cells compared to control suggests a role for ARIH1 in hnRNP-E1 degradation. The identification of hnRNP-E1 as a candidate substrate of ARIH1 led to the characterization of a novel function for this ubiquitin ligase in EMT induction and cancer progression. We demonstrate a delayed induction of EMT and reduced invasion in mammary epithelial cells silenced for ARIH1. Conversely, ARIH1 overexpression promoted EMT induction and invasion. ARIH1 silencing in breast cancer cells significantly attenuated cancer cell stemness in vitro and tumor formation in vivo. Finally, we utilized miniTurboID proximity labeling to identify novel ARIH1 interactors that may contribute to ARIH1’s function in EMT induction and cancer progression.

The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS

“…ARIH1 is a component of the CRL system and regulates cancer progression and xenophagy of cytosolic bacteria 46 , 49 – 51 . Since ARIH1 interacts with cGAS that mediates innate antiviral responses, we investigated the role of ARIH1 in HSV-1- or cytoplasmic DNA-triggered immune signaling.…”

“…Recent studies have revealed a suppressive role of ARIH1 in tumorigenesis 49 , 51 . A more recent report has shown that ARIH1 catalyzes ubiquitination and degradation of PD-L1 and thereby promotes anti-tumor immunity and that the expression of ARIH1 is severely suppressed in lung adenocarcinoma biopsies 51 .…”

A robust CD8+ T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma

“…For cancer cells, Vimentin consequently led to metastasis and immune escape through the expression of PD-L1 in LUAD by triggering the TGF-b/SMAD2 signaling (44). In addition, ARIH1 (or HHARI) known as a ubiquitin-protein ligase, contributed to EMT induction and breast cancer progression (45,46). However, Wu et al found that the overexpression of ARIH1 could suppress tumor growth and promote cytotoxic T cell activation by inducing PD-L1 degradation (47).…”

Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer

“…The tumor-suppressive RBP, hnRNP-E1, is known to modulate splicing and translation of the epithelial to mesenchymal transition (EMT)-associated transcripts and to play a major role in the control of epithelial cell plasticity during cancer progression. The ARIH1, an E3 ubiquitin ligase, can target and interfere with the activity of this RBP by degrading it and promoting breast cancer progression [ 109 ]. The RBP DDX41 is a tumor suppressor that opposes double-strand DNA breaks, genomic instability, and R-loop-dependent replication stress by preferentially binding RNA–DNA hybrids and unwinding RNA–DNA hybrids in R-loops, and also reduces the fragility of DNA in promoter regions [ 39 ].…”