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, Dong Hyeon Lee

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15 Citations (Scopus)

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. UTXUTY 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.

Original languageEnglish
Pages (from-to)63252-63260
Number of pages9
JournalOncotarget
Volume7
Issue number39
DOIs
Publication statusPublished - 2016 Jan 1

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All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Ahn, J., Kim, K. H., Park, S., Ahn, Y. H., Kim, H. Y., Yoon, H., Lee, J. H., Bang, D., & Lee, D. H. (2016). Target sequencing and CRISPR/Cas editing reveal simultaneous loss of UTX and UTY in urothelial bladder cancer. Oncotarget, 7(39), 63252-63260. https://doi.org/10.18632/oncotarget.11207