Hepatic loss of CerS2 induces cell division defects via a mad2-mediated pathway.
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ABSTRACT:
SUBMITTER: Cao M
PROVIDER: S-EPMC8797468 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
Publications
Hepatic loss of CerS2 induces cell division defects via a mad2-mediated pathway.
Cao Mingjun M Zhang Shaohua S Lam Sin Man SM Shui Guanghou G
Clinical and translational medicine 20220101 1
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Project description:PurposeTo explore the underlying mechanism of primordial follicle loss in the early period following ovarian tissue transplantation (OTT).MethodsBNIP3 was selected through bioinformatic protocols, as the hub gene related to autophagy during OTT. BNIP3 and autophagy in mice ovarian grafts and in hypoxia-mimicking KGN cells were detected using immunohistochemistry, transmission electron microscopy (TEM), western blotting, qPCR, and fluorescence staining. The regulatory role played by BNIP3 overexpression and the silencing of KGN cells in autophagy via the mTOR/ULK1 pathway was investigated.ResultsUltrastructure examination showed that autophagic vacuoles increased after mice ovarian auto-transplantation. The BNIP3 and autophagy-related proteins (Beclin-1, LC3B, and SQSTM1/p62) in mice ovarian granulosa cells of primordial follicle from ovarian grafts were altered compared with the control. Administration of an autophagy inhibitor in mice decreased the depletion of primordial follicles. In vitro experiments indicated that BNIP3 and autophagy activity were upregulated in KGN cells treated with cobalt chloride (CoCl2). The overexpression of BNIP3 activated autophagy, whereas the silencing of BNIP3 suppressed it and reversed the autophagy induced by CoCl2 in KGN cells. Western blotting analysis showed the inhibition of mTOR and activation of ULK1 in KGN cells treated with CoCl2 and in the overexpression of BNIP3, and the opposite results following BNIP3 silencing. The activation of mTOR reversed the autophagy induced by BNIP3 overexpression.ConclusionsBNIP3-induced autophagy is crucial in primordial follicle loss during OTT procedure, and BNIP3 is a potential therapeutic target for primordial follicle loss after OTT.
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Project description:BackgroundShugoshin-like protein 2 (SGOL2) is a centromeric protein that ensures the correct and orderly process of mitosis by protecting and maintaining centripetal adhesions during meiosis and mitosis. Here, we examined the potential role of SGOL2 in cancers, especially in hepatocellular carcinoma (HCC).MethodsOne hundred ninety-nine normal adjacent tissues and 202 HCC samples were collected in this study. Human HCC cells (SK-HEP-1 and HEP-3B) were employed in the present study. Immunohistochemistry, immunofluorescence, western blot, Co-Immunoprecipitation technique, and bioinformatic analysis were utilized to assess the role of SGOL2 in HCC development process.ResultsOverexpression of SGOL2 predicted an unfavorable prognosis in HCC by The Cancer Genome Atlas database (TCGA), which were further validated in our two independent cohorts. Next, 47 differentially expressed genes positively related to both SGOL2 and MAD2 were identified to be associated with the cell cycle. Subsequently, we demonstrated that SGOL2 downregulation suppressed the malignant activities of HCC in vitro and in vivo. Further investigation showed that SGOL2 promoted tumor proliferation by regulating MAD2-induced cell-cycle dysregulation, which could be reversed by the MAD2 inhibitor M2I-1. Consistently, MAD2 upregulation reversed the knockdown effects of SGOL2-shRNA in HCC. Moreover, we demonstrated that SGOL2 regulated MAD2 expression level by forming a SGOL2-MAD2 complex, which led to cell cycle dysreuglation of HCC cells.ConclusionSGOL2 acts as an oncogene in HCC cells by regulating MAD2 and then dysregulating the cell cycle, providing a potential therapeutic target in HCC.
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Project description:We have examined the mechanism of normal DNA methyltransferase 1 (DNMT1) degradation as well as its mechanism of dysregulation in cancer. We have previously reported that DNMT1 protein levels were elevated and abnormally stabilized because of defective degradation through its N-terminal destruction domain. Here, we report that DNMT1 was abnormally stabilized in several cancer cell lines and that, in cells with normal DNMT1 destruction, depletion of CDC20 or FZR1 (two substrate recognition adaptor components of the anaphase-promoting complex) resulted in stabilization of DNMT1 that was partially dependent on the N-terminal destruction domain, thus implicating this cell cycle regulator in the destruction of DNMT1. MAD2, an inhibitor of CDC20, was shown to stabilize DNMT1 levels, and overexpression of MAD2, a consequence of retinoblastoma (RB) pathway dysregulation, was shown to correlate with impaired G(1) phase DNMT1 destruction and RB inactivation by hyperphosphorylation in several normal and cancer cell lines. Furthermore, in a series of 85 cases of human breast cancer, a moderately strong, but highly significant, correlation between MAD2 and DNMT1 immunohistochemical staining was observed, yielding a Spearman rank order correlation coefficient of 0.37 (P<0.001). This suggests that RB pathway inactivation, a common dysfunction in cancer cells, may be the underlying cause of DNMT1 dysregulation.
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Project description:A balance between bone formation by osteoblasts and bone resorption by osteoclasts is necessary to maintain bone health and homeostasis. As a cancer of plasma cells, multiple myeloma (MM) is accompanied with rapid bone loss and fragility fracture. Bortezomib has been used as a first-line for treating MM for decades. Recently, the potential protection of bortezomib on osteoporosis (OP) is reported; however, the specific mechanism involving bortezomib-mediated antiosteoporotic effect is undetermined. In the present study, we assessed the effects of in vitro bortezomib treatment on osteogenesis and osteoclastogenesis and the protective effect on bone loss in ovariectomized (OVX) mice. Our results indicated that bortezomib treatment increased osteogenic differentiation of MC3T3-E1 cells as evidenced by increased levels of matrix mineralization and osteoblast-specific markers. In bortezomib-treated bone marrow monocytes (BMMs), osteoclast differentiation was suppressed, substantiated by downregulated tartrate-resistant acid phosphatase- (TRAP-) positive multinucleated cells, areas of actin rings, pit formation, and osteoclast-specific genes. Mechanistically, bortezomib exerted a protective effect against OP through the Smad ubiquitination regulatory factor- (SMURF-) mediated ubiquitination pathway. Furthermore, in vivo intraperitoneal injection of bortezomib attenuated the bone microarchitecture in OVX mice. Accordingly, our findings corroborated that bortezomib might have future applications in the treatment of postmenopausal OP.
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