| The deubiquitinase USP11 promotes ovarian cancer chemoresistance by stabilizing BIPOvarian cancer is a common gynecological malignancy with a low 5-year survival rate.Due to the early clinical symptoms are not obvious,most patients are diagnosed at advanced stage.Chemoresistance is a major problem in the treatment of ovarian cancer patients and leads to poor prognosis,but its underlying mechanism remains elusive.The dynamic balance of ubiquitination and deubiquitination is critical for protein stability and subcellular localization.In recent years,a multitude of studies have shown that deubiquinases regulate the stability of various oncoproteins and tumor suppressor proteins and participate in the process of tumorigenesis and development.Therefore,it is of great significance to find new therapeutic targets and improve the prognosis of ovarian cancer patients by revealing the specific function and mechanism of deubiquitinases in the process of ovarian cancer chemoresistance.Here,we find high expression level of USP11 is related to the poor prognosis and chemoresistance in ovarian cancer by performing immunohistochemistry staining.To investigate the function of USP11,we constructed stably overexpressed or knockdown USP11 ovarian cancer cell lines.The results exhibited that forced expression of USP11 significantly promotes cell viability and inhibits cell apoptosis with carboplatinum(CBP)treatment,while suppression of USP11 exhibits the opposite effects.We further found that the efficacy of CBP could be inhibit by USP11 in vivo by performing subcutaneous xenografting assay.Mechanistically,we figured out that USP11 interacts with BIP by mass spectrometry.Co-IP analysis determined that USP11 interacts with BIP and regulates the protein level of BIP.At the same time,the GST pulldown assay showed the directly interaction between USP11 and BIP.Since USP11 is a member of the deubiquitinase family,we further found that USP11 regulates BIP through the deubiquitination pathway.Overexpression USP11 can significantly reduce the ubiquitination level of BIP while the inactive mutant USP11C318A lost this effect.Consistently,deletion of USP11 in ovarian cancer cells could abridge the half-life of BIP.Then we blocked USP11 by pharmacological inhibitor Mitoxantrone(MTX)in ovarian cancer cells and the protein level of BIP was decreased.In addition,when we knockdown BIP in USP11 overexpressed ovarian cancer cells,the function of USP11 in promoting chemoresistance was relieved.Finally,we detected the expression level of USP11 and BIP in 70 cases of ovarian cancer patients.The expression level of USP11 and BIP was significantly positive correlated,and the high expression of USP11/BIP was associated with poor prognosis in ovarian cancer.In summary,our findings revealed the function of USP11 in ovarian cancer and elucidated the molecular mechanisms underlying the involvement of USP11 in ovarian cancer chemoresistance.We also identified the USP11-BIP axis as a potential therapeutic target for ovarian cancer in the future.Identification and functional study of driver genes regulated by super enhancer in ESCCEsophageal cancer is a type of cancer with Chinese characteristics.More than 50%of the deaths caused by esophageal cancer in the world occur in China.In China,esophageal squamous cell carcinoma(ESCC)is the main type,which is characterized by strong invasiveness and poor prognosis.In our country,the main problems of esophageal cancer diagnosis and treatment are lack of specific markers and effective targets,the difficulty of early diagnosis and the limited treatment methods.Genome sequencing has facilitated the development of precision tumor therapy,however,the genetic drivers of esophageal cancer remain unclear,so new dimensions are needed to identify and develop therapeutic leads.The enhancer is a fragment of DNA sequence on the genome that can cooperate with transcription factors to enhance gene expression.Super enhancers(SE)are composed of a large number of linear enhancer clusters,usually spanning several kilobases in size.Super-enhancers are important regulators of cell recognition genes,and the in-depth analysis of their regulatory mechanisms will help reveal the mechanism of tumorigenesis and development.In particular,it provides a theoretical framework for the discovery of new targets and targeted drugs for tumors that lack known genetic drivers and are thus difficult to treat.Therefore,the identification and in-depth analysis of superenhancers in esophageal cancer lacking dominant driving genes and targeting strategies will provide an important molecular basis for individualized and precise diagnosis and treatment of esophageal cancer.In this study,we performed epigenetic multi-omics and transcriptome analysis on 11 esophageal squamous cancer cell lines and 3 normal esophageal epithelial cell lines.The enhancer/super-enhancer landscape was mapped by H3K4me1/H3K27Ac ChIP-Seq,and the ESCC specific super-enhancer map was obtained by applying the computational framework,and the esophageal cancer-specific super-enhancer was identified.Next,we selected tumor-specific enhancers with significant enhancer characteristics,combined ATAC-seq,three-dimensional genome(Hi-C)technology and RNA-seq to find target genes regulated by tumor-specific super-enhancers.Here,we identified five genes CREG2,ENKUR,HAS3,KCNK1 and PAPL which regulated by ESCC specific superenhancers for further functional validation.Through in vitro and in vivo functional experiments,it was determined that these five genes indeed play oncogene functions in esophageal cancer.In conclusion,our study integrated and analyzed multidimensional omics data to identify ESCC specific super enhancer-oncogene pairs,and further screened the key oncogenes driving the malignant proliferation of ESCC cells through functional verification,thereby identifying potential drug targets.This provides a theoretical basis for explaining the molecular mechanism of esophageal carcinogenesis and developing therapeutic/combination therapy strategies targeting super-enhancer regulatory pathways. |
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