Molecular Mechanism Of USP11 Promoting The Proliferation Of Breast Cancer

Breast cancer is one of the most common malignant tumors among women.In 2018,about 2.1 million women were diagnosed with breast cancer and 626,679 women died from breast cancer.The number of breast cancer patients worldwide grew by more than1.6 million from 1980 to 2010,with an annual growth rate of 3.1%,and this growth trend will continue to increase.Improvements in multimodal therapy have led to increasing chances for cure in 70%-80% of patients with non-metastatic disease.In contrast,due to distant organ metastasis,advanced breast cancer is not considered curable using existing available treatments.USP11 is a member of the ubiquitin-specific protease family.USP11 partcipates in DNA damage repair,cell proliferation,cell apoptosis and cell signal transduction through stabilizing specific substrate via deubiquitination.Current studies have shown that USP11 has dual role in tumors.On one hand,USP11 can inhibit tumourgenesis by maintaining the stability of VGLL4,Mgl-1,nuclear p21,PTEN,etc.On the other hand,USP11 can promote cell proliferation and metastasis by stabilizing ALK5 and BRCA1/2,XIAP,Snail,etc.USP11 expresses highly in clinical breast cancer tissues and some cell lines,and is associated with poor 5-year survival rate and prognosis,plays an important role in promoting breast cancer cell proliferation,invasion and metastasis,but the detailed molecular mechanism has not been fully clarified.To establish the relationship between USP11 and breast cancer,we first identified that USP11 had the biological function of promoting breast cancer cell proliferation,and clarified that USP11 was highly expressed in breast cancer tissues by using tissue microarrays.To reveal the molecular function of USP11 in breast cancer cells,we performed immunofluorescence and immunoprecipitation experiments,and found that USP11 and p21 were co-localized and interacted in the cytoplasm of breast cancer cells.To uncovered whether USP11 regulates p21,USP11 was overexpressed or knocked down in breast cancer cells,and the data showed that USP11 could regulate the cytoplasmic p21 at the protein level by applying cellular protein nucleoplasm separation experiment and q PCR experiment.Meanwhile,knocked down of USP11 followed by the addition of proteasome inhibitor MG132 abolished the regulation of p21 by USP11,indicating that USP11 regulates the p21 through the ubiquitin-proteasome pathway.To establish the functional role of the USP11-p21 axis mediating breast cancer cellproliferation,we performed cell proliferation assays.The results showed that overexpressed p21 could reverse the inhibition of cell proliferation caused by knockdown of USP11,wheres knockdown of p21 could reverse the promoting of USP11 on breast cancer cells.Taken together,our studies suggest that USP11 can promote the proliferation of breast cancer cells by regulating cytoplasmic p21.This study clarified the relationship between USP11 and breast cancer,and revealed that the molecular mechanism of USP11 in promoting the proliferation of breast cancer cells by regulating cytoplasmic p21,and provides a new target and entry point for the prevention and treatment of breast cancer.