Universität zu Köln

Kobayashi, Yuta ORCID: 0000-0002-2029-8292, Bustos, Matias A. ORCID: 0000-0001-9625-1127, Shoji, Yoshiaki, Jachimowicz, Ron D., Shiloh, Yosef and Hoon, Dave S. B. (2022). Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor. Cells, 11 (20). BASEL: MDPI. ISSN 2073-4409

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Abstract

Ubiquilin-4 (UBQLN4) is a proteasomal shuttle factor that directly binds to ubiquitylated proteins and delivers its cargo to the 26S proteasome for degradation. We previously showed that upregulated UBQLN4 determines the DNA damage response (DDR) through the degradation of MRE11A. However, the regulatory mechanism at DNA level, transcriptionally and post-transcriptional levels that control UBQLN4 mRNA levels remains unknown. In this study, we screened 32 solid tumor types and validated our findings by immunohistochemistry analysis. UBQLN4 is upregulated at both mRNA and protein levels and the most significant values were observed in liver, breast, ovarian, lung, and esophageal cancers. Patients with high UBQLN4 mRNA levels had significantly poor prognoses in 20 of 32 cancer types. DNA amplification was identified as the main mechanism promoting UBQLN4 upregulation in multiple cancers, even in the early phases of tumor development. Using CRISPR screen datasets, UBQLN4 was identified as a common essential gene for tumor cell viability in 81.1% (860/1,060) of the solid tumor derived cell lines. Ovarian cancer cell lines with high UBQLN4 mRNA levels were platinum-based chemotherapy resistant, while they were more sensitive to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi). Our findings highlight the utilities of UBQLN4 as a significant pan-cancer theranostic factor and a precision oncology biomarker for DDR-related drug resistance.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kobayashi, Yuta UNSPECIFIED orcid.org/0000-0002-2029-8292 UNSPECIFIED Bustos, Matias A. UNSPECIFIED orcid.org/0000-0001-9625-1127 UNSPECIFIED Shoji, Yoshiaki UNSPECIFIED UNSPECIFIED UNSPECIFIED Jachimowicz, Ron D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shiloh, Yosef UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoon, Dave S. B. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-675794
DOI:	10.3390/cells11203311
Journal or Publication Title:	Cells
Volume:	11
Number:	20
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2073-4409
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CANCER; PROTEIN; DEGRADATION; TARGETS Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67579