BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5.

Junying Qin,Zhongmei Zhou,Chunyan Wang,Rong Liu,Hailin Zhang,Ceshi Chen,Guangzhe Ge,Dingyun You,Ming Shao,Wenlin Chen,Houjun Xia,Zhixiang Fan

doi:10.1038/ncomms9471

Abstract

The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth. Here we show that, in breast cancer cells, KLF5 is stabilized by the deubiquitinase (DUB) BAP1. With a genome-wide siRNA library screen of DUBs, we identify BAP1 as a bona fide KLF5 DUB. BAP1 interacts directly with KLF5 and stabilizes KLF5 via deubiquitination. KLF5 is in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression partially by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be rescued partially by ectopic expression of KLF5. Collectively, our findings not only identify BAP1 as the DUB for KLF5, but also reveal a critical mechanism that regulates KLF5 expression in breast cancer. Our findings indicate that BAP1 could be a potential therapeutic target for breast and other cancers.

Highlights

The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth
Our previous studies demonstrated that KLF5 promoted cell proliferation, survival and tumour growth, partially through inducing the transcription of downstream target genes, such as fibroblast growth factor-binding protein 1 (FGF-BP)[22,23,24] and microsomal prostaglandin E2 synthase 125
Our results suggest that BAP1 and KLF5 are potential therapeutic targets for breast cancer

Summary

Introduction

The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth. Our previous studies demonstrated that KLF5 promoted cell proliferation, survival and tumour growth, partially through inducing the transcription of downstream target genes, such as fibroblast growth factor-binding protein 1 (FGF-BP)[22,23,24] and microsomal prostaglandin E2 synthase 1 (mPGES1)[25]. These findings collectively define KLF5 as a potent therapeutic target for basal TNBC and other cancers. Our results suggest that BAP1 and KLF5 are potential therapeutic targets for breast cancer

Methods

Results

Conclusion