Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT85D4H9)

• DOT Name: Transmembrane 9 superfamily member 4 (TM9SF4)
• Synonyms: Tumor cannibalism associated protein 1
• Gene Name: TM9SF4
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chronic obstructive pulmonary disease
  Neoplasm
  Autism spectrum disorder
  Inflammatory bowel disease
  Metastatic melanoma
  Myelodysplastic syndrome
• UniProt ID: TM9S4_HUMAN
• Pfam ID: PF02990
• Sequence:
  MATAMDWLPWSLLLFSLMCETSAFYVPGVAPINFHQNDPVEIKAVKLTSSRTQLPYEYYS
  LPFCQPSKITYKAENLGEVLRGDRIVNTPFQVLMNSEKKCEVLCSQSNKPVTLTVEQSRL
  VAERITEDYYVHLIADNLPVATRLELYSNRDSDDKKKEKDVQFEHGYRLGFTDVNKIYLH
  NHLSFILYYHREDMEEDQEHTYRVVRFEVIPQSIRLEDLKADEKSSCTLPEGTNSSPQEI
  DPTKENQLYFTYSVHWEESDIKWASRWDTYLTMSDVQIHWFSIINSVVVVFFLSGILSMI
  IIRTLRKDIANYNKEDDIEDTMEESGWKLVHGDVFRPPQYPMILSSLLGSGIQLFCMILI
  VIFVAMLGMLSPSSRGALMTTACFLFMFMGVFGGFSAGRLYRTLKGHRWKKGAFCTATLY
  PGVVFGICFVLNCFIWGKHSSGAVPFPTMVALLCMWFGISLPLVYLGYYFGFRKQPYDNP
  VRTNQIPRQIPEQRWYMNRFVGILMAGILPFGAMFIELFFIFSAIWENQFYYLFGFLFLV
  FIILVVSCSQISIVMVYFQLCAEDYRWWWRNFLVSGGSAFYVLVYAIFYFVNKLDIVEFI
  PSLLYFGYTALMVLSFWLLTGTIGFYAAYMFVRKIYAAVKID
• Function: Associates with proteins harboring glycine-rich transmembrane domains and ensures their efficient localization to the cell surface. Regulates the assembly and activity of V-ATPase in colon cancer cells via its interaction with V-type proton ATPase subunit H (ATP6V1H) and contributes to V-ATPase-mediated pH alterations in cancer cells which play an important role in drug resistance and invasiveness of colon cancer cells. Plays an important role in an atypical phagocytic activity of metastatic melanoma cells called cannibalism and is involved in the pH regulation of the intracellular vesicles in tumor cells.
• Tissue Specificity: Highly expressed in metastatic melanoma cells whereas it is undetectable in primary melanoma cells, healthy skin tissues and peripheral blood lymphocytes. Expressed in CD34(+) hematopoietic progenitor cells and during monocyte and granulocyte differentiation. Overexpressed in acute myeloid leukemia, in particular in those displaying granulocytic differentiation (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[4]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[5]
Metastatic melanoma	DISSL43L	Limited	Altered Expression	[6]
Myelodysplastic syndrome	DISYHNUI	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Transmembrane 9 superfamily member 4 (TM9SF4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane 9 superfamily member 4 (TM9SF4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane 9 superfamily member 4 (TM9SF4).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transmembrane 9 superfamily member 4 (TM9SF4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane 9 superfamily member 4 (TM9SF4).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transmembrane 9 superfamily member 4 (TM9SF4).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Transmembrane 9 superfamily member 4 (TM9SF4).	[8]

1 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 increases the methylation of Transmembrane 9 superfamily member 4 (TM9SF4).	[13]

References

• [1] The human homologue of Dictyostelium discoideum phg1A is expressed by human metastatic melanoma cells.EMBO Rep. 2009 Dec;10(12):1348-54. doi: 10.1038/embor.2009.236. Epub 2009 Nov 6.
• [2] Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells.Oncogene. 2019 Jul;38(29):5778-5791. doi: 10.1038/s41388-019-0846-y. Epub 2019 Jun 27.
• [3] Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.Nat Genet. 2017 Mar;49(3):426-432. doi: 10.1038/ng.3752. Epub 2017 Feb 6.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012 Nov 1;491(7422):119-24. doi: 10.1038/nature11582.
• [6] Human TM9SF4 Is a New Gene Down-Regulated by Hypoxia and Involved in Cell Adhesion of Leukemic Cells.PLoS One. 2015 May 11;10(5):e0126968. doi: 10.1371/journal.pone.0126968. eCollection 2015.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] 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.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] 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.
• [13] 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.