The E3 ligase HERC4 is overexpressed in human breast cancer and its expression levels correlated with the prognosis of breast cancer patients. However, the roles of HERC4 in mammary tumorigenesis remain unclear. Here ...The E3 ligase HERC4 is overexpressed in human breast cancer and its expression levels correlated with the prognosis of breast cancer patients. However, the roles of HERC4 in mammary tumorigenesis remain unclear. Here we demonstrate that the knockdown of HERC4 in human breast cancer cells dramatically suppressed their proliferation, survival, migration, and tumor growth in vivo, while the overexpression of HERC4 promoted their aggressive tumorigenic activities. HERC4 is a new E3 ligase for the tumor suppressor LATS1 and destabilizes LATS1 by promoting the ubiquitination of LATS1 miRNA-136-5p and miRNA-1285-5p, expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, are directly involved in suppressing the expression of HERC4. In summary, we discover a miRNA-HERC4- LATS1 pathway that plays important roles in the pathogenesis of breast cancer and represents new therapeutic targets for human breast cancer.展开更多
Pluripotent stem cells(PSCs)are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body,and thus hold great promise for regenerative medicine.To achieve their clinic...Pluripotent stem cells(PSCs)are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body,and thus hold great promise for regenerative medicine.To achieve their clinical potential,it is critical for PSCs to maintain genomic stability during the extended proliferation.The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells.In response to DNA damage or oncogenic stress,p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest,apoptosis,and senescence to prevent the passage of genetic mutations to the daughter cells.p53 is also required to maintain the genomic stability of PSCs.However,in response to the genotoxic stresses,a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency,providing mechanisms to maintain the genomic stability of the self-renewing PSCs.In addition,the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress.In summary,the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.展开更多
基金National Natural Science Foundation of China (Grant Nos. 81430032 and U1601222)the leading talents of Guangdong Province Program (No. 00201516)Major basic research developmental project of the Natural Science Foundation of Guangdong Provin ce.
文摘The E3 ligase HERC4 is overexpressed in human breast cancer and its expression levels correlated with the prognosis of breast cancer patients. However, the roles of HERC4 in mammary tumorigenesis remain unclear. Here we demonstrate that the knockdown of HERC4 in human breast cancer cells dramatically suppressed their proliferation, survival, migration, and tumor growth in vivo, while the overexpression of HERC4 promoted their aggressive tumorigenic activities. HERC4 is a new E3 ligase for the tumor suppressor LATS1 and destabilizes LATS1 by promoting the ubiquitination of LATS1 miRNA-136-5p and miRNA-1285-5p, expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, are directly involved in suppressing the expression of HERC4. In summary, we discover a miRNA-HERC4- LATS1 pathway that plays important roles in the pathogenesis of breast cancer and represents new therapeutic targets for human breast cancer.
基金supported by the National Natural Science Foundation of China(Grant Nos.815300045,81871197,81930084,81430032,U1601222)the National High Technology Research and Development Program(863 Program)(No.2015AA020310)+2 种基金Development and Reform Commission of Shenzhen Municipality(S2016004730009)Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06S638)Shenzhen“Sanming”Project of Medicine(SZSM201602102).
文摘Pluripotent stem cells(PSCs)are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body,and thus hold great promise for regenerative medicine.To achieve their clinical potential,it is critical for PSCs to maintain genomic stability during the extended proliferation.The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells.In response to DNA damage or oncogenic stress,p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest,apoptosis,and senescence to prevent the passage of genetic mutations to the daughter cells.p53 is also required to maintain the genomic stability of PSCs.However,in response to the genotoxic stresses,a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency,providing mechanisms to maintain the genomic stability of the self-renewing PSCs.In addition,the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress.In summary,the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.
