Universität zu Köln

Murakami, Tomohiro, Shoji, Yoshiaki ORCID: 0000-0003-3074-1398, Nishi, Tomohiko, Chang, Shu-Ching, Jachimowicz, Ron D., Hoshimoto, Sojun, Ono, Shigeshi, Shiloh, Yosef, Takeuchi, Hiroya, Kitagawa, Yuko, Hoon, Dave S. B. and Bustos, Matias A. (2021). Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma. Mol. Oncol., 15 (4). S. 1069 - 1088. HOBOKEN: WILEY. ISSN 1878-0261

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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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Murakami, Tomohiro UNSPECIFIED UNSPECIFIED UNSPECIFIED Shoji, Yoshiaki UNSPECIFIED orcid.org/0000-0003-3074-1398 UNSPECIFIED Nishi, Tomohiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Chang, Shu-Ching UNSPECIFIED UNSPECIFIED UNSPECIFIED Jachimowicz, Ron D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoshimoto, Sojun UNSPECIFIED UNSPECIFIED UNSPECIFIED Ono, Shigeshi UNSPECIFIED UNSPECIFIED UNSPECIFIED Shiloh, Yosef UNSPECIFIED UNSPECIFIED UNSPECIFIED Takeuchi, Hiroya UNSPECIFIED UNSPECIFIED UNSPECIFIED Kitagawa, Yuko UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoon, Dave S. B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bustos, Matias A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-598696
DOI:	10.1002/1878-0261.12929
Journal or Publication Title:	Mol. Oncol.
Volume:	15
Number:	4
Page Range:	S. 1069 - 1088
Date:	2021
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1878-0261
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59869