Molecule Information

General Information of the Molecule (ID: Mol00257)

• Name: Polycomb complex protein BMI-1 (BMI1) ,Homo sapiens
• Synonyms: Polycomb group RING finger protein 4; RING finger protein 51; PCGF4; RNF51
• Molecule Type: Protein
• Gene Name: BMI1
• Gene ID: 100532731
• Location: chr10:22316388-22329542[+]
• Sequence:
  MHRTTRIKITELNPHLMCVLCGGYFIDATTIIECLHSFCKTCIVRYLETSKYCPICDVQV
  HKTRPLLNIRSDKTLQDIVYKLVPGLFKNEMKRRRDFYAAHPSADAANGSNEDRGEVADE
  DKRIITDDEIISLSIEFFDQNRLDRKVNKDKEKSKEEVNDKRYLRCPAAMTVMHLRKFLR
  SKMDIPNTFQIDVMYEEEPLKDYYTLMDIAYIYTWRRNGPLPLKYRVRPTCKRMKISHQR
  DGLTNAGELESDSGSDKANSPAGGIPSTSSCLPSPSTPVQSPHPQFPHISSTMNGTSNSP
  SGNHQSSFANRPRKSSVNGSSATSSG
• Function: Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A. In the PRC1-like complex, regulates the E3 ubiquitin-protein ligase activity of RNF2/RING2.
• Uniprot ID: BMI1_HUMAN
• Ensembl ID: ENSG00000269897
• HGNC ID: HGNC:48326

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Tongue cancer [1]

• Resistant Disease: Tongue cancer [ICD-11: 2B62.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: SHH/GLI1 signaling pathway; Activation; hsa05217
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of BMI1 alters cell proliferation, apoptosis and stem cell self-renewal and correlates with the invasion and metastasis of several human cancers. BMI1 overexpression due to reduction of miR-200b and miR-15b may result in chemotherapy-induced EMT in TSCCs via these pathways.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [2]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Laryngeal cancer [3]

• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: AMC-HN-8 cells; Larynx; Homo sapiens (Human); CVCL_5966
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR128a decreases the expression of BMI1 and suppresses the resistance of laryngeal cancer cells to paclitaxel & cisplatin.

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast cancer [4]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: MDAMB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL assay; BrdU assay; MTT assay
• Mechanism Description: Overexpressing miR-15a sensitizes MDAMB-231 cells to the chemotherapeutic drug cisplatin via inhibiting BMI1 and downregulating MET.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Endometrial cancer [5]

• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Resistant Drug: Docetaxel
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Disease-free survival analysis
• Mechanism Description: Recently, Dong et al. demonstrated that loss of BMI1 in endometrial cancer cells reduces expression of drug resistance gene MRP1, suggesting that BMI1 is required for the drug resistance. Overexpression of BMI1 rescues tumor cells from the apoptosis induced by Okadaic acid and Epigallocatechin-3-gallate, well-known apoptotic agents.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Prostate cancer [6]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bmi-1 is expressed at a high level in PCa. miR-200b plays a pivotal role in PCa at least in part via downregulation of the oncogene Bmi-1, inhibition of Bmi-1 enhanced the antitumor activity of docetaxel in PCa cells.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Breast cancer [7]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Celltiter glo assay
• Mechanism Description: TrkB is signaling via PLCGamma, the MAP kinases or PI3k and Akt. Phosphorylation of Akt plays a pivotal role in cell survival and anti-apoptotic signaling by phosphorylating and thereby inhibiting pro-apoptotic factors like Bad or Caspase 9. Bmi1 may mediate resistance via other pathways than p53, for instance via the PI3k/Akt pathway. TrkB and Bmi1 Protein Expression is Hampered by Overexpression of miR-200c in MDA-MB 436 Cells, and cause thr resistance to Doxorubicin.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [8]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reduction of miR-128 in BT-ICs leads to overexpression of Bmi-1 and ABCC5, two independent targets of miR-128. Ectopic expression of miR-128 decreases cell viability and increases apoptosis and DNA damage in the presence of doxorubicin, hence sensitizes BT-ICs to chemotherapy.

Disease Class: Leiomyosarcoma [9]

• Resistant Disease: Leiomyosarcoma [ICD-11: 2B58.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Spheroid formation; Activation; hsa04140
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: SK-UT-1 cells; Uterus; Homo sapiens (Human); CVCL_0533
• In Vivo Model: BALB/c-nu female mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay; Flow cytometry assay; Transwell migration and invasion assay
• Mechanism Description: The expression levels of CSC-related markers in CD133+ subpopulation derived from SK-UT-1 cells, Western blotting was employed to detect the expression levels of CD44, ALDH1, BMI1, and Nanog. Expectedly, researchers found that CD133+subpopulation had higher expression levels of CD44, ALDH1, BMI1, and Nanog compared with those of CD133 subpopulation. Collectively, the above-mentioned results suggested that CD133+ subpopulation derived from SK-UT-1 cells possessed capabilities of resistance to apoptosis after treatment with DXR, as well as stemness feature of cancer stem-like cells.

Disease Class: Leiomyosarcoma [9]

• Resistant Disease: Leiomyosarcoma [ICD-11: 2B58.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Spheroid formation; Activation; hsa04140
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: SK-UT-1 cells; Uterus; Homo sapiens (Human); CVCL_0533
• In Vivo Model: BALB/c-nu female mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay; Flow cytometry assay; Transwell migration and invasion assay
• Mechanism Description: The expression levels of CSC-related markers in CD133+ subpopulation derived from SK-UT-1 cells, Western blotting was employed to detect the expression levels of CD44, ALDH1, BMI1, and Nanog. Expectedly, researchers found that CD133+subpopulation had higher expression levels of CD44, ALDH1, BMI1, and Nanog compared with those of CD133 subpopulation. Collectively, the above-mentioned results suggested that CD133+ subpopulation derived from SK-UT-1 cells possessed capabilities of resistance to apoptosis after treatment with DXR, as well as stemness feature of cancer stem-like cells.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Breast cancer [10]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-200c and miR-203 overexpression in breast cancer cells downregulated Bmi1 expression accompanied with reversion of resistance to 5-Fu mediated by Bmi1.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [11]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Missense mutation; p.S324Y
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Laryngeal cancer [3]

• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: AMC-HN-8 cells; Larynx; Homo sapiens (Human); CVCL_5966
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR128a decreases the expression of BMI1 and suppresses the resistance of laryngeal cancer cells to paclitaxel & cisplatin.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [12]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Rapamycin signaling pathway; Inhibition; hsa04211
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase activity assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR128 can effectively suppress PTX-resistant lung cancer stem cells via inhibition of BMI-1 and MUC1-C, thus downregulating the PI3k/AkT pathway and the rapamycin pathway.

References

• Ref 1: MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene. 2012 Jan 26;31(4):432-45. doi: 10.1038/onc.2011.263. Epub 2011 Jul 4.
• Ref 2: Deregulation of miR-128 in ovarian cancer promotes cisplatin resistance. Int J Gynecol Cancer. 2014 Oct;24(8):1381-8. doi: 10.1097/IGC.0000000000000252.
• Ref 3: Overexpressed miR-128a enhances chemoradiotherapy to laryngeal cancer cells and its correlation with BMI1. Future Oncol. 2018 Mar;14(7):611-620. doi: 10.2217/fon-2017-0542. Epub 2017 Nov 30.
• Ref 4: Regulating BMI1 expression via miRNAs promote Mesenchymal to Epithelial Transition (MET) and sensitizes breast cancer cell to chemotherapeutic drug. PLoS One. 2018 Feb 2;13(2):e0190245. doi: 10.1371/journal.pone.0190245. eCollection 2018.
• Ref 5: Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 2012 Mar;30(3):372-8. doi: 10.1002/stem.1035.
• Ref 6: miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1. Oncol Rep. 2014 Feb;31(2):910-8. doi: 10.3892/or.2013.2897. Epub 2013 Dec 5.
• Ref 7: miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression. PLoS One. 2012;7(11):e50469. doi: 10.1371/journal.pone.0050469. Epub 2012 Nov 29.
• Ref 8: Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5. Clin Cancer Res. 2011 Nov 15;17(22):7105-15. doi: 10.1158/1078-0432.CCR-11-0071. Epub 2011 Sep 27.
• Ref 9: Identification and characterization of a subpopulation of CD133(+) cancer stem-like cells derived from SK-UT-1 cells .Cancer Cell Int. 2021 Mar 8;21(1):157. doi: 10.1186/s12935-021-01817-y. 10.1186/s12935-021-01817-y
• Ref 10: A Bmi1-miRNAs cross-talk modulates chemotherapy response to 5-fluorouracil in breast cancer cells. PLoS One. 2013 Sep 9;8(9):e73268. doi: 10.1371/journal.pone.0073268. eCollection 2013.
• Ref 11: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. doi: 10.1038/nature12065. Epub 2013 Apr 7.
• Ref 12: MicroRNA-128 suppresses paclitaxel-resistant lung cancer by inhibiting MUC1-C and BMI-1 in cancer stem cells. Oncotarget. 2017 Nov 30;8(66):110540-110551. doi: 10.18632/oncotarget.22818. eCollection 2017 Dec 15.