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

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 m...

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Bibliographic Details
Published in:Oncotarget 2016-09, Vol.7 (39), p.63252-63260
Main Authors: Ahn, Jinwoo, Kim, Kwang Hyun, Park, Sanghui, Ahn, Young-Ho, Kim, Ha Young, Yoon, Hana, Lee, Ji Hyun, Bang, Duhee, Lee, Dong Hyeon
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Cell Proliferation
Chromatin - chemistry
Clustered Regularly Interspaced Short Palindromic Repeats
CRISPR-Cas Systems
Epigenesis, Genetic
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HEK293 Cells
Histone Demethylases - metabolism
Humans
Lentivirus - genetics
Male
Minor Histocompatibility Antigens - metabolism
Mutation
Nuclear Proteins - metabolism
Prospective Studies
Research Paper
Urinary Bladder Neoplasms - metabolism
X Chromosome Inactivation
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.11207