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Breast cancer is among the most common malignant cancers in women. B‐cell‐specific Moloney murine leukemia virus integration site 1 (BMI‐1) is a transcriptional repressor that has been shown to be involved in tumorigenesis, the cell cycle, and stem cell maintenance. In our study, increased expression of BMI‐1 was found in both human triple negative breast cancer and luminal A‐type breast cancer tissues compared with adjacent tissues. We also found that knockdown of BMI‐1 significantly suppressed cell proliferation and migration in vitro and in vivo. Further mechanistic research demonstrated that BMI‐1 directly bound to the promoter region of CDKN2D/BRCA1 and inhibited its transcription in MCF‐7/MDA‐MB‐231. More importantly, we discovered that knockdown of CDKN2D/BRCA1 could promote cell proliferation and migration after repression by PTC‐209. Our results reveal that BMI‐1 transcriptionally suppressed BRCA1 in TNBC cell lines whereas, in luminal A cell lines, CDKN2D was the target gene. This provides a reference for the precise treatment of different types of breast cancer in clinical practice. BMI‐1 promotes proliferation and migration via transcriptional inhibition of cyclin‐dependent kinase inhibitor 2D (CDKN2D) in luminal A‐type breast cancer but via transcriptional inhibition of breast cancer susceptibility gene 1 (BRCA1) in TNBC.

The transcriptional repressor Bmi‐1 is involved in cell‐cycle regulation and cell senescence, the deficiency of which has been shown to cause oxidative stress. This study investigated whether Bmi‐1 deficiency plays a role in promoting disc degeneration and the effect of treatment with antioxidant N‐acetylcysteine (NAC) on intervertebral disc degeneration. Bmi‐1−/− mice were treated with the antioxidant NAC, supplied in drinking water (Bmi‐1−/−+NAC). For in vitro experiments, mouse intervertebral discs were cultured under low oxygen tension and serum‐limiting conditions in the presence of tumour necrosis factor α and interleukin 1β in order to mimic degenerative insult. Disc metabolism parameters in these in vitro and in vivo studies were evaluated by histopathological, immunohistochemical and molecular methods. Bmi‐1−/− mice showed lower collagen Ⅱ and aggrecan levels and higher collagen Ⅹ levels than wild‐type and Bmi‐1−/−+NAC mice. Bmi‐1−/− mice showed significantly lower superoxide dismutase (SOD)‐1, SOD‐2, glutathione peroxidase (GPX)‐1 and GPX‐3 levels than their wild‐type littermates and Bmi‐1−/−+ NAC mice. Relative to Bmi‐1−/− mice, the control and Bmi‐1−/−+NAC mice showed significantly lower p16, p21, and p53 levels. These results demonstrate that Bmi‐1 plays an important role in attenuating intervertebral disc degeneration in mice by inhibiting oxidative stress and cell apoptosis.

With the increase in the aging population, senile osteoporosis (SOP) has become a major global public health concern. Here, it is found that Prx1 and Bmi‐1 co‐localized in trabecular bone, bone marrow cavity, endosteum, and periosteum. Prx1‐driven Bmi‐1 knockout in bone‐marrow mesenchymal stem cells (BMSCs) reduced bone mass and increased bone marrow adiposity by inhibiting osteoblastic bone formation, promoting osteoclastic bone resorption, downregulating the proliferation and osteogenic differentiation of BMSCs, and upregulating the adipogenic differentiation of BMSCs. However, Prx1‐driven Bmi‐1 overexpression showed a contrasting phenotype to Prx1‐driven Bmi‐1 knockout in BMSCs. Regarding mechanism, Bmi‐1‐RING1B bound to DNMT3A and promoted its ubiquitination and inhibited DNA methylation of Runx2 at the region from 45047012 to 45047313 bp, thus promoting the osteogenic differentiation of BMSCs. Moreover, Bmi‐1‐EZH2 repressed the transcription of Cebpa by promoting H3K27 trimethylation at the promoter region −1605 to −1596 bp, thus inhibiting the adipogenic differentiation of BMSCs. It is also found that Prx1‐driven Bmi‐1 overexpression rescued the SOP induced by Prx1‐driven Bmi‐1 knockout in BMSCs. Thus, Bmi‐1 functioned as a hub protein in the epigenetic regulation of BMSCs differentiation to delay bone aging. The Prx1‐driven Bmi‐1 overexpression in BMSCs can be used as an approach for the translational therapy of SOP. Bmi‐1 epigenetically orchestrates osteogenic and adipogenic differentiation of bone‐marrow mesenchymal stem cells (BMSCs) to prevent senile osteoporosis (SOP). Prx1‐driven Bmi‐1 overexpression in BMSCs rescues the SOP phenotype induced by Prx1‐driven Bmi‐1 knockout in BMSCs. The Prx1‐driven Bmi‐1 overexpression in BMSCs can be used as an approach for the translational therapy of SOP. (Image created with BioRender.com).

Background: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. Aims: To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. Results: LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. BMI-1 silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In in vitro 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. Conclusions: By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance.

BMI‐1 (B‐cell‐specific Moloney murine leukemia virus integration site 1) has been implicated in both normal and cancer cell biology. While the canonical function of BMI‐1 involves epigenetic repression, novel extranuclear functions have been recently reported. In the present study, we demonstrate that the phosphorylation of BMI‐1 in diffuse intrinsic pontine glioma (DIPG) cells occurs in M phase and that it triggers simultaneous translocation of the phosphorylated BMI‐1 to the cytoplasm. This translocation is mediated by the RanGTP‐dependent transporter CRM1, also known as exportin. Furthermore, we uncovered a previously unidentified nuclear export signal (NES) in the BMI‐1 protein, suggesting an active transport type of modified BMI‐1 mediated by CRM1. These findings associate BMI‐1 phosphorylation with its trafficking in M phase. Collectively, this study sheds light on the molecular mechanisms underlying BMI‐1 functions in DIPG, thereby potentially paving the way for the development of targeted therapeutic strategies related to M phase progression. The schematic illustrates BMI‐1 phosphorylation during M phase, which triggers its translocation from the nucleus to the cytoplasm. In cycling cells, BMI‐1 functions within the PRC1 complex to mediate H2A K119 monoubiquitination. Following PTC596‐induced M phase arrest, phosphorylated BMI‐1 dissociates from PRC1 and is exported to the cytoplasm via its NES through the CRM1 pathway.

The PI3K/AKT pathway is frequently activated in endometrial carcinoma. BMI‐1 (B‐lymphoma Mo‐MLV insertion region 1) protein affects expression of PTEN (phosphatase and tensin homolog) in some cancers, but its significance for endometrial tumorigenesis is not known. The objective of this study was to determine the relationship between BMI‐1 and expression of factors affecting AKT (protein kinase B) phosphorylation level in endometrial cancer. The expression of proteins and mRNAs was investigated in endometrial cancer specimens and samples of non‐neoplastic endometrial tissue by Western blot and RT‐PCR, respectively. The impact of BMI‐1 down‐regulation on AKT phosphorylation and expression of genes coding for several phosphatases were studied in HEC1A cells. The results showed that BMI‐1 depletion caused increase in PHLPP1 and PHLPP2 (PH domain and leucine‐rich repeat protein phosphatases 1/2) expression and decrease in phospho‐AKT (pAKT) level. In more advanced tumours with higher metastatic potential, the expression of BMI‐1 was lower compared to tumours less advanced and without lymph node metastasis. There were significant inverse correlations between BMI‐1 and PHLPPs, especially PHLPP1 in normal endometrial samples. The inverse correlation between BMI‐1 and PHLPP1/PHLPP2 expression was observed in PTEN positive but not PTEN negative cancers. Low PHLPP2 expression in tumours predicted poorer overall survival. BMI‐1 impacts on AKT phosphorylation level in endometrial cells by regulation of PHLPP expression.

Summary To determine whether Bmi‐1 deficiency could lead to renal tubulointerstitial injury by mitochondrial dysfunction and increased oxidative stress in the kidney, 3‐week‐old Bmi‐1‐/‐ mice were treated with the antioxidant N‐acetylcysteine (NAC, 1 mg mL−1) in their drinking water, or pyrro‐quinoline quinone (PQQ, 4 mg kg−1 diet) in their diet for 2 weeks, and their renal phenotypes were compared with vehicle‐treated Bmi1‐/‐ and wild‐type mice. Bmi‐1 was knocked down in human renal proximal tubular epithelial (HK2) cells which were treated with 1 mm NAC for 72 or 96 h, and their phenotypes were compared with control cells. Five‐week‐old vehicle‐treated Bmi‐1‐/‐ mice displayed renal interstitial fibrosis, tubular atrophy, and severe renal function impairment with decreased renal cell proliferation, increased renal cell apoptosis and senescence, and inflammatory cell infiltration. Impaired mitochondrial structure, decreased mitochondrial numbers, and increased oxidative stress occurred in Bmi‐1‐/‐ mice; subsequently, this caused DNA damage, the activation of TGF‐β1/Smad signaling, and the imbalance between extracellular matrix synthesis and degradation. Oxidative stress‐induced epithelial‐to‐mesenchymal transition of renal tubular epithelial cells was enhanced in Bmi‐1 knocked down HK2 cells. All phenotypic alterations caused by Bmi‐1 deficiency were ameliorated by antioxidant treatment. These findings indicate that Bmi‐1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance and will be a novel therapeutic target for preventing renal tubulointerstitial injury.

Aims Senescence‐associated pathological cardiac hypertrophy (SA‐PCH) is associated with upregulation of foetal genes, fibrosis, senescence‐associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA‐PCH, and whether Bmi‐1‐RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA‐PCH. Methods and results Bmi‐1‐deficient (Bmi‐1−/−), transgenic Bmi‐1 overexpressing (Bmi‐1Tg) and wild‐type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA‐PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi‐1‐RING1B and autophagy are negatively related to SA‐PCH. Bmi‐1 deficiency promoted GATA4‐dependent SA‐PCH by increasing GATA4 protein and hypertrophy‐related molecules transcribed by GATA4 such as ANP and BNP. Bmi‐1 deficiency stimulated NF‐κB‐p65‐dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. Bmi‐1 overexpression repressed GATA4‐dependent SA‐PCH. GATA4 degraded by Bmi‐1 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi‐1 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi‐1 and LC3B. With increased p16 protein levels, ANP‐, BNP‐ and GATA4‐positive cells or areas increased; however, LC3B‐positive cells or areas decreased in human myocardium. GATA4 is ubiquitinated after combining with Bmi‐1‐RING1B, which is then recognised by p62, is translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA‐PCH and cardiac dysfunction by reducing GATA4‐dependent hypertrophy and SASP‐related molecules. Bmi‐1 combined with RING1B (residues 1–179) and C‐terminus of GATA4 (residues 206–443 including zinc finger domains) through residues 1–95, including a RING‐HC‐finger. RING1B combined with C‐terminus of GATA4 through the C‐terminus (residues 180–336). Adeno‐associated viral vector serotype 9 (AAV9)‐cytomegalovirus (CMV)‐Bmi‐1‐RING1B treatment significantly attenuated GATA4‐dependent SA‐PCH through promoting GATA4 autophagic degradation. Conclusions Bmi‐1‐RING1B maintained cardiac function and prevented SA‐PCH by promoting selective autophagy for degrading GATA4. Translational perspective AAV9‐CMV‐Bmi‐1‐RING1B could be used for translational gene therapy to ubiquitinate GATA4 and prevent GATA4‐dependent SA‐PCH. Also, the combined domains between Bmi‐1‐RING1B and GATA4 in aging cardiomyocytes could be therapeutic targets for identifying stapled peptides in clinical applications to promote the combination of Bmi‐1‐RING1B with GATA4 and the ubiquitination of GATA4 to prevent SA‐PCH and heart failure. We found that degradation of cardiac GATA4 by Bmi‐1 was mainly dependent on autophagy rather than proteasome, and autophagy agonists metformin and rapamycin could ameliorate the SA‐PCH, suggesting that activation of autophagy with metformin or rapamycin could also be a promising method to prevent SA‐PCH. GATA4 is ubiquitinated after combining with Bmi‐1‐RING1B, which is then recognized by p62, translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA‐PCH and cardiac dysfunction by reducing GATA4‐dependent hypertrophy and SASP‐related molecules. Bmi‐1 combined with RING1B (residues 1‐179) and GATA4 (C‐terminus from residues 206 to 443 including zinc finger domains) through residues 1‐95 including a RING‐HC‐finger. RING1B combined with GATA4 (C‐terminus from residues 206 to 443 including zinc finger domains) through the C‐terminus (residues 180‐336). AAV9‐CMV‐Bmi‐1‐RING1B is used for gene therapy to prevent GATA4‐dependent SA‐PCH. The combined domains between Bmi‐1‐RING1B and GATA4 could be therapeutic targets for identifying stapled peptides to promote the combination of them.

Background Glioblastoma (GBM) is the most common primary brain tumor in adults and has a median survival of less than 15 months. Advancements in the field of epigenetics have expanded our understanding of cancer biology and helped explain the molecular heterogeneity of these tumors. B‐cell‐specific Moloney murine leukemia virus insertion site‐1 (Bmi‐1) is a member of the highly conserved polycomb group (PcG) protein family that acts as a transcriptional repressor of multiple genes, including those that determine cell proliferation and differentiation. We hereby aim to explore the specific involvement of Bmi‐1 in glioma pathogenesis. Methods A comprehensive narrative review was employed using “PubMed”. Articles were screened for relevance specific keywords and medical subject headings (MeSH) terms related to the topic combined with Boolean operators (AND, OR). Keywords and MeSH terms included the following: “glioma”, “polycomb repressive complex 1”, and “Bmi1”. Results In GBMs, several reports have shown that Bmi‐1 is overexpressed and might serve as a prognostic biomarker. We find that Bmi‐1 participates in regulating the gene expression and chromatin structure of several tumor suppressor genes or cell cycle inhibitors. Bmi‐1 has a critical role in modulating the tumor microenvironment to support the plasticity of GBM stem cells.We explore Bmi‐1's involvement in maintaining glioma stem cell (GSC) proliferation and senescence evasion upon regulating the chromatin structure of several tumor suppressor genes, cell cycle inhibitors, or stem cell genes in tumor cells. Additionally, we analyze Bmi‐1's involvement in modulating the DNA repair machinery or activating anti‐apoptotic pathways to confer therapy resistance. Importantly, our research discusses the importance of targeting Bmi‐1 that could be a promising therapeutic target for GBM treatment. Bmi‐1 activates and interacts with NF‐κB to promote angiogenesis and invasion, regulates the INK4a‐ARF locus, and interacts with various microRNAs to influence tumor progression and proliferation. In addition, Bmi‐1 confers radioresistance and chemotherapy by promoting cell senescence evasion and DNA repair. Conclusion Bmi‐1 regulates self‐renewal, proliferation, and differentiation of GBM cells, promoting stemness and therapy resistance. Targeting Bmi‐1 could be a promising novel therapeutic strategy for GBM treatment.

CD146 expression is gradually decreased during the long‐term expansion of human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs) in culture, and enforced CD146 downregulation accelerated senescence in hUCB‐MSCs, which affected their multilineage differentiation potential, growth, and stemness. These data indicate a possible role for CD146 in inhibiting senescence in hUCB‐MSCs, which may occur via the regulation of Bmi‐1, Id1, and Twist1 expression. CD146 may be a novel marker for predicting senescence in hUCB‐MSCs, and it could be valuable in quality‐control assessments and for improving the therapeutic potential of hUCB‐MSC‐based therapy. Therapeutic applications of mesenchymal stem cells (MSCs) for treating various diseases have increased in recent years. To ensure that treatment is effective, an adequate MSC dosage should be determined before these cells are used for therapeutic purposes. To obtain a sufficient number of cells for therapeutic applications, MSCs must be expanded in long‐term cell culture, which inevitably triggers cellular senescence. In this study, we investigated the surface markers of human umbilical cord blood‐derived MSCs (hUCB‐MSCs) associated with cellular senescence using fluorescence‐activated cell sorting analysis and 242 cell surface‐marker antibodies. Among these surface proteins, we selected the melanoma cell adhesion molecule (MCAM/CD146) for further study with the aim of validating observed expression differences and investigating the associated implications in hUCB‐MSCs during cellular senescence. We observed that CD146 expression markedly decreased in hUCB‐MSCs following prolonged in vitro expansion. Using preparative sorting, we found that hUCB‐MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence‐associated β‐galactosidase, compared with that observed in hUCB‐MSCs with low‐level CD146 expression. In contrast, CD146 downregulation with small interfering RNAs enhanced the senescence phenotype. In addition, CD146 suppression in hUCB‐MSCs caused downregulation of other cellular senescence regulators, including Bmi‐1, Id1, and Twist1. Collectively, our results suggest that CD146 regulates cellular senescence; thus, it could be used as a therapeutic marker to identify senescent hUCB‐MSCs. Significance One of the fundamental requirements for mesenchymal stem cell (MSC)‐based therapies is the expansion of MSCs during long‐term culture because a sufficient number of functional cells is required. However, long‐term growth inevitably induces cellular senescence, which potentially causes poor clinical outcomes by inducing growth arrest and the loss of stem cell properties. Thus, the identification of markers for evaluating the status of MSC senescence during long‐term culture may enhance the success of MSC‐based therapy. This study provides strong evidence that CD146 is a novel and useful marker for predicting senescence in human umbilical cord blood‐derived MSCs (hUCB‐MSCs), and CD146 can potentially be applied in quality‐control assessments of hUCB‐MSC‐based therapy.