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

Autor: Matias A. Bustos, Sojun Hoshimoto, Ron D. Jachimowicz, Tomohiko Nishi, Yoshiaki Shoji, Dave S.B. Hoon, Yuko Kitagawa, Yosef Shiloh, Hiroya Takeuchi, Shu Ching Chang, Shigeshi Ono, Tomohiro Murakami
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Cancer Research
Esophageal Neoplasms
medicine.medical_treatment
0302 clinical medicine
Japan
Medicine
esophageal cancer
Research Articles
MRE11 Homologue Protein
biology
MRE11
Nuclear Proteins
chemoresistance
General Medicine
Middle Aged
Esophageal cancer
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Neoadjuvant Therapy
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Immunohistochemistry
Female
Esophageal Squamous Cell Carcinoma
Research Article
neoadjuvant chemotherapy
ubiquilin‐4
medicine.drug
Ubiquilin 4
DNA damage
lcsh:RC254-282
03 medical and health sciences
Cell Line
Tumor
Genetics
Humans
Cisplatin
Chemotherapy
business.industry
medicine.disease
digestive system diseases
MRE11A
030104 developmental biology
MRN complex
Drug Resistance
Neoplasm
Cancer research
biology.gene
Carrier Proteins
business
Zdroj: Mol Oncol
Molecular Oncology, Vol 15, Iss 4, Pp 1069-1087 (2021)
Molecular Oncology
ISSN: 1878-0261
1574-7891
Popis: 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
We unraveled a novel mechanism driving resistance to cisplatin‐based chemotherapies in esophageal squamous cell carcinoma (ESCC) and demonstrated their clinical utility. Briefly, we showed that cisplatin treatment promotes Meiotic Recombination 11 Homolog A (MRE11A) ubiquitination. Binding of ubiquilin‐4 (UBQLN4) to ubiquitinated‐MRE11A increased MRE11A degradation, thereby promoting cisplatin resistance. Both MRE11A and UBQLN4 can predict neoadjuvant chemotherapy response and serve as prognostic markers in ESCC patients.
Databáze: OpenAIRE
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