RPRD1A stabilizes NRF2 and aggravates HCC progression through competing with p62 for TRIM21 binding

Abstract

NRF2 is the master transcriptional activator of cytoprotective genes and Kelch-like ECH-associated protein 1 (Keap1), a biosensor for electrophiles and oxidation, promotes NRF2 degradation in unstressed conditions. SQSTM1/p62, an oncogenic protein aberrantly accumulated in hepatocellular carcinoma (HCC), binds and sequestrates Keap1, leading to the prevention of NRF2 degradation. Here, we show that p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A) is highly expressed in HCC tumors and correlated with aggressive clinicopathological features. RPRD1A competitively interacts with TRIM21, an E3 ubiquitin ligase of p62, resulting in the decrease of p62 ubiquitination and the increased sequestration for Keap1. Therefore, RPRD1A enhances the nuclear translocation of NRF2, which induces gene expression for counteracting oxidative stress, maintaining cancer cells survival, and promoting HCC development. Moreover, disturbing the redox homeostasis of cancer cells by genetic knockdown of RPRD1A sensitizes cancer cells to platinum-induced cell death. Our study reveals RPRD1A is involved in the oxidative stress defense program and highlights the therapeutic benefits of targeting pathways that support antioxidation.

The emerging roles of TRIM21 in coordinating cancer metabolism, immunity and cancer treatment

“…TRIM21 directly interacts with and ubiquitinates p62 at the K7 residue to abolish Keap1 sequestration, downregulating the Nrf2 redox pathway to induce cell death in response to oxidative stress (130). In line with this, TRIM21-deficient heart tissues and cells enhance p62mediated sequestration of Keap1 to protect themselves from doxorubicin-induced ferroptosis (130)(131)(132). Phosphatase and tensin homologue (PTEN), a tumor suppressor protein that regulates Nrf2 expression in a Keap1-independent manner (133), can be upregulated by nuclear Prothymosin-a (PTMA) at the transcriptional level.…”

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks

“…Transcriptional changes, e.g., the loss of RBM47, are associated with KEAP1 mRNA stabilization, and the existence of alternatively spliced NRF2 variants also contributes to NRF2 augmentation [7,8]. Furthermore, sequestration of KEAP1 by NRF2competitive-binding proteins including TRIM21, RPRD1A, and FAM129B was found in NRF2-addicted cancer models [9][10][11]. Thus, it remains to explore the best way to define the NSCLC with high NRF2 addition.…”

Research progress of TRIMs protein family in tumors

“…TRIM21 was highly expressed in HCC, and TRIM21 genetic ablation protected the liver from oxidative injury and reduced the occurrence of HCC by suppressing the p62-Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway . Another study reported that p15INK4b-related sequence/regulation of nuclear pre-mRNA domaincontaining protein 1A (RPRD1A) interacted with TRIM21 by increasing the aggregation of p62 and Keap1 to promote nuclear translocation of Nrf2, which further contributes to the progression of HCC (Feng et al, 2021). However, the down-regulation of TRIM21 was associated with a poor prognosis in patients with HCC (Ding et al, 2015).…”