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

Publication Title

Mol Oncol

Authors

Tomohiro Murakami, Department of Translational Molecular Medicine, Division of Molecular Oncology, Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
Yoshiaki Shoji, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.Follow
Tomohiko Nishi, Department of Translational Molecular Medicine, Division of Molecular Oncology, Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
Shu-Ching Chang, Medical Data Research Center Providence Health and Services at Providence Saint Joseph's Health, Portland, OR, USA.Follow
Ron D Jachimowicz
Sojun Hoshimoto, Department of Translational Molecular Medicine, Division of Molecular Oncology, Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
Shigeshi Ono, Department of Translational Molecular Medicine, Division of Molecular Oncology, Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
Yosef Shiloh
Hiroya Takeuchi
Yuko Kitagawa
Dave Hoon, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.Follow
Matias Bustos, Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.Follow

Document Type

Article

Publication Date

2-19-2021

Keywords

california; santa monica; psjhc; jwci; portland; ppmc; oregon

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.

Clinical Institute

Cancer

Clinical Institute

Digestive Health

Specialty/Research Institute

Oncology

Specialty/Research Institute

Surgery