USP10 Promotes KLF4 De-ubiquitination And Inhabits Migration/Invasion Of Breast Cancer Cells

Breast cancer is a disease that severely threatens women’s health.Histopathology has recognized that breast cancer is a heterogeneous disease with intratumoral and inter-tumoral variability.With the development of technology,such as microarray analysis and new generation of DNA sequencing,the diversity of this disease has been further described based on its characteristics in molecular biology and genetics.Currently,breast cancer can be classified into several subtypes,including but not limited to: Luminal A,Luminal B,HER2-overexpression,and triple-negative cancer.This classification is mainly based on the expression status of estrogen receptor(ER),progeston receptor(PR)and Her-2 receptor.The cause of death in the vast majority of breast cancer patients is due to the metastasis of tumors from the original site to some important organs,such as liver,spleen,lung,etc.If the metastasis of breast cancer can be effectively inhibited,the survival of breast cancer patients will be greatly improved.Therefore,it becomes very important to understand the mechanism of breast cancer metastasis at the molecular level.The understanding of this disease and its metastasis is also crucial for developing the early diagnosis method and finding effective drug targets to cure the disease.The Kruppel-like family of transcription factors(KLFs)include multiple proteins that have the similar Zinc-finger DNA-binding domain and function in gene expression regulation.They express in many different tissues and organs.Studies have shown that KLFs participate in many physiological processes regulation,such as proliferation,development,differentiation,embryo development etc..They also involves in pathogenesis of many diseases,including cancer and inflammatory disease.KLF4 is one of the important member of the Kruppel-like factor family.By binding to the promoter sequence of different target gene,KLF4 plays dual roles in gene regulation;either activating or suppressing gene expression.In cancer,KLF4 can function as a tumorpromoter as well as a tumor suppressor.However,KLF4 is considered as inhibition factor for EMT and cancer cell migration/invasion.It has been reported that KLF4 can be modified by ubiquitination.Because ubiquitination is a reversible process,there should be an opposite processdeubiquitination,in vivo.Deubiquitination is catalyzed by deubiquitination enzymes(DUBs).However,so far there is no any reports regarding the existence of the KLF4 deubiquitinase.Based on previous work in this laboratory,my current research focuses on studying the interaction between the deubiquitinating enzymes USP10 and KLF4 and the regulation of USP10 on KLF4.The function of USP10 in EMT and breast cancer cell migration/invasion also are studied.The main goal of this study is to lay a foundation for future development of drugs to inhibiting breast cancer metastasis and treating this disease.The major results are as follows:1.There is the interaction between USP10 and KLF4.The interaction domains of these two proteins are identified.2.USP10 up-regulates KLF4 expression by promoting deubiquitination of KLF4.3.USP10 inhibits breast cancer cell EMT,and cell metastasis and invasion.