Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma

Abstract

Resistance to standard cisplatin‐based chemotherapies leads to worse survival outcomes for patients with esophageal squamous cell carcinoma (ESCC). Therefore, there is an urgent need to understand the aberrant mechanisms driving resistance in ESCC tumors. We hypothesized that ubiquilin‐4 (UBQLN4), a protein that targets ubiquitinated proteins to the proteasome, regulates the expression of Meiotic Recombination 11 Homolog A (MRE11A), a critical component of the MRN complex and DNA damage repair pathways. Initially, immunohistochemistry analysis was conducted in specimens from patients with ESCC (n = 120). In endoscopic core ESCC biopsies taken from 61 patients who underwent neoadjuvant chemotherapy (NAC) (5‐fluorouracil and cisplatin), low MRE11A and high UBQLN4 protein levels were associated with reduced pathological response to NAC (P < 0.001 and P < 0.001, respectively). Multivariable analysis of surgically resected ESCC tissues from 59 patients revealed low MRE11A and high UBLQN4 expression as independent factors that can predict shorter overall survival [P = 0.01, hazard ratio (HR) = 5.11, 95% confidence interval (CI), 1.45–18.03; P = 0.02, HR = 3.74, 95% CI, 1.19–11.76, respectively]. Suppression of MRE11A expression was associated with cisplatin resistance in ESCC cell lines. Additionally, MRE11A was found to be ubiquitinated after cisplatin treatment. We observed an amplification of UBQLN4 gene copy numbers and an increase in UBQLN4 protein levels in ESCC tissues. Binding of UBQLN4 to ubiquitinated‐MRE11A increased MRE11A degradation, thereby regulating MRE11A protein levels following DNA damage and promoting cisplatin resistance. In summary, MRE11A and UBQLN4 protein levels can serve as predictors for NAC response and as prognostic markers in ESCC patients.

A Comprehensive Multiomics Analysis Identified Ubiquilin 4 as a Promising Prognostic Biomarker of Immune-Related Therapy in Pan-Cancer

“…It was reported that overexpression of UBQLN4 in neuroblastoma cells increased the sensitivity of PARP inhibitors [ 4 ]. However, Murakami et al found that knocking down UBQLN4 in esophageal squamous cell carcinoma increased cisplatin sensitivity [ 7 ], suggesting different roles of UBQLN4 played in various drugs. In line with previous studies, our results showed that there was a positive correlation between UBQLN4 CNV and olaparib sensitivity.…”

“…Gradually, the role of UBQLN4 in cancers attracted increasing attention [ 6 , 7 ], although theories behind are premature. It was reported that the increase of UBQLN4 in neuroblastoma and melanoma decreased survival [ 4 ].…”

UBQLN4 promotes STING proteasomal degradation during cisplatin‐induced DNA damage in triple‐negative breast cancer

“…We have previously reported that UBQLN4 levels affect cisplatin sensitivity. 5,6 UBQLN4 levels were associated with increased cisplatin resistance in TNBC cell lines (Figure 1H). UBQLN4 depletion did not induce significant transcriptional changes in TNBC cell lines (Figure S1B-F) or reduce cellular proliferation (Figure S1G-J); however, it increased the sensitivity to cisplatin, whereas UBQLN4-OV led to cisplatin resistance (Figure 1I-K).…”

Post-Translational Modification of MRE11: Its Implication in DDR and Diseases

“…Further analysis provides a rationale for this finding by showing that UBQLN4 overexpression protects cells from acute genotoxic stress through enhancing the NHEJ-mediated sealing of DSBs, as NHEJ-driven mutagenesis is likely to be selected in cancer cells due to its error-prone mechanism [85]. Moreover, UBQLN4 binds to MRE11 and promotes MRE11 degradation, leading to cisplatin-resistance in cancer cells, i.e., esophageal squamous cell carcinoma (ESCC) [93]. Similarly, MRE11 ubiquitination is also involved in bladder cancer.…”