Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEAAUBY)

• DOT Name: Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1)
• Synonyms: Hematopoietic PBX-interacting protein
• Gene Name: PBXIP1
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Ductal carcinoma
  Epithelial ovarian cancer
  Head-neck squamous cell carcinoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Osteoarthritis
• UniProt ID: PBIP1_HUMAN
• Sequence:
  MASCPDSDNSWVLAGSESLPVETLGPASRMDPESERALQAPHSPSKTDGKELAGTMDGEG
  TLFQTESPQSGSILTEETEVKGTLEGDVCGVEPPGPGDTVVQGDLQETTVVTGLGPDTQD
  LEGQSPPQSLPSTPKAAWIREEGRCSSSDDDTDVDMEGLRRRRGREAGPPQPMVPLAVEN
  QAGGEGAGGELGISLNMCLLGALVLLGLGVLLFSGGLSESETGPMEEVERQVLPDPEVLE
  AVGDRQDGLREQLQAPVPPDSVPSLQNMGLLLDKLAKENQDIRLLQAQLQAQKEELQSLM
  HQPKGLEEENAQLRGALQQGEAFQRALESELQQLRARLQGLEADCVRGPDGVCLSGGRGP
  QGDKAIREQGPREQEPELSFLKQKEQLEAEAQALRQELERQRRLLGSVQQDLERSLQDAS
  RGDPAHAGLAELGHRLAQKLQGLENWGQDPGVSANASKAWHQKSHFQNSREWSGKEKWWD
  GQRDRKAEHWKHKKEESGRERKKNWGGQEDREPAGRWKEGRPRVEESGSKKEGKRQGPKE
  PPRKSGSFHSSGEKQKQPRWREGTKDSHDPLPSWAELLRPKYRAPQGCSGVDECARQEGL
  TFFGTELAPVRQQELASLLRTYLARLPWAGQLTKELPLSPAFFGEDGIFRHDRLRFRDFV
  DALEDSLEEVAVQQTGDDDEVDDFEDFIFSHFFGDKALKKRSGKKDKHSQSPRAAGPREG
  HSHSHHHHHRG
• Function: Regulator of pre-B-cell leukemia transcription factors (BPXs) function. Inhibits the binding of PBX1-HOX complex to DNA and blocks the transcriptional activity of E2A-PBX1. Tethers estrogen receptor-alpha (ESR1) to microtubules and allows them to influence estrogen receptors-alpha signaling.
• Tissue Specificity: Expressed in early hematopoietic precursors.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[1]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[3]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[3]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[4]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[8]
Osteoarthritis	DIS05URM	Limited	Biomarker	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1) decreases the response to substance of Irinotecan.	[25]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[15]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1).	[24]

References

• [1] HPIP silencing inhibits TGF-1-induced EMT in lung cancer cells.Int J Mol Med. 2017 Feb;39(2):479-483. doi: 10.3892/ijmm.2017.2851. Epub 2017 Jan 5.
• [2] Hematopoietic PBX-interacting protein (HPIP) is over expressed in breast infiltrative ductal carcinoma and regulates cell adhesion and migration through modulation of focal adhesion dynamics.Oncogene. 2015 Aug 27;34(35):4601-12. doi: 10.1038/onc.2014.389. Epub 2014 Dec 8.
• [3] Expression and clinicopathological significance of hematopoietic pre-B cell leukemia transcription factor-interacting protein in cervical carcinoma.Pathol Res Pract. 2018 Sep;214(9):1340-1344. doi: 10.1016/j.prp.2017.07.031. Epub 2017 Aug 1.
• [4] HPIP Silencing Prevents Epithelial-Mesenchymal Transition Induced by TGF-1 in Human Ovarian Cancer Cells.Oncol Res. 2016;24(1):33-9. doi: 10.3727/096504016X14575597858654.
• [5] Knockdown of HPIP Inhibits the Proliferation and Invasion of Head-and-Neck Squamous Cell Carcinoma Cells by Regulating PI3K/Akt Signaling Pathway.Oncol Res. 2016;24(3):153-60. doi: 10.3727/096504016X14612603423476.
• [6] HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation.Cell Oncol (Dordr). 2017 Apr;40(2):133-144. doi: 10.1007/s13402-016-0308-2. Epub 2016 Dec 30.
• [7] CSR1 suppresses tumor growth and metastasis of human hepatocellular carcinoma via inhibition of HPIP.Eur Rev Med Pharmacol Sci. 2017 Oct;21(17):3813-3820.
• [8] Hematopoietic PBX-interacting protein is a substrate and an inhibitor of the APC/C-Cdc20 complex and regulates mitosis by stabilizing cyclin B1.J Biol Chem. 2019 Jun 28;294(26):10236-10252. doi: 10.1074/jbc.RA118.006733. Epub 2019 May 17.
• [9] Hematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis.Nat Commun. 2019 Jan 18;10(1):313. doi: 10.1038/s41467-018-08277-5.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.