Oncotarget

Research Papers:

Target sequencing and CRISPR/Cas editing reveal simultaneous loss of UTX and UTY in urothelial bladder cancer

Jinwoo Ahn, Kwang Hyun Kim, Sanghui Park, Young-Ho Ahn, Ha Young Kim, Hana Yoon, Ji Hyun Lee, Duhee Bang _ and Dong Hyeon Lee

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Oncotarget. 2016; 7:63252-63260. https://doi.org/10.18632/oncotarget.11207

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Abstract

Jinwoo Ahn1,*, Kwang Hyun Kim2,*, Sanghui Park3, Young-Ho Ahn4, Ha Young Kim1, Hana Yoon2, Ji Hyun Lee5, Duhee Bang1, Dong Hyeon Lee2

1Department of Chemistry, Yonsei University, Seoul, Korea

2Department of Urology, Ewha Womans University School of Medicine, Seoul, Korea

3Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea

4Department of Molecular Medicine, Ewha Womans University School of Medicine, Seoul, Korea

5Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Korea

*Co-first authors

Correspondence to:

Duhee Bang, email: [email protected]

Dong Hyeon Lee, email: [email protected]

Keywords: urinary bladder neoplasm, chromatin remodeling, UTX, UTY, epigenesis

Received: January 14, 2016     Accepted: July 26, 2016     Published: August 11, 2016

ABSTRACT

UTX is a histone demethylase gene located on the X chromosome and is a frequently mutated gene in urothelial bladder cancer (UBC). UTY is a paralog of UTX located on the Y chromosome. We performed target capture sequencing on 128 genes in 40 non-metastatic UBC patients. UTX was the most frequently mutated gene (30%, 12/40). Of the genetic alterations identified, 75% were truncating mutations. UTY copy number loss was detected in 8 male patients (22.8%, 8/35). Of the 9 male patients with UTX mutations, 6 also had copy number loss (66.7%). To evaluate the functional roles of UTX and UTY in tumor progression, we designed UTX and UTY single knockout and UTX-UTY double knockout experiments using a CRISPR/Cas9 lentiviral system, and compared the proliferative capacities of two UBC cell lines in vitro. Single UTX or UTY knockout increased cell proliferation as compared to UTX-UTY wild-type cells. UTX-UTY double knockout cells exhibited greater proliferation than single knockout cells. These findings suggest both UTX and UTY function as dose-dependent suppressors of UBC development. While UTX escapes X chromosome inactivation in females, UTY may function as a male homologue of UTX, which could compensate for dosage imbalances.


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