Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3FPH0)

• DOT Name: Killin (KLLN)
• Gene Name: KLLN
• Related Disease:
  Carcinoma
  Chromosomal disorder
  Clear cell renal carcinoma
  Coronary atherosclerosis
  Coronary heart disease
  Endometrial cancer
  Hereditary breast carcinoma
  Kidney cancer
  Neoplasm
  Non-small-cell lung cancer
  Psoriasis
  Renal carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Endometrial carcinoma
  Sarcoma
  Soft tissue sarcoma
  Cowden disease
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Cowden syndrome 4
• UniProt ID: KILIN_HUMAN
• Sequence:
  MDRPGPGSARPGRTVHVWGYRVEWKVRNGRKLQPSEWAGRGDLGGFKRRWKDTRATVGTT
  FRRRSRVSLVGELSKFPLPSDSSGGKSSSSFARGALAWCRQRNPNPSCAAAETGARTSLP
  KERCRGWRLGNWLHKHPHPNTCPRLPACWLPPILTERGERVPKLVPLLACYPKSKPKD
• Function: DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis. Has the ability to inhibit DNA synthesis and S phase arrest coupled to apoptosis. Has affinity to both double- and single-stranded DNA.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Altered Expression	[1]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[4]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[4]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[5]
Hereditary breast carcinoma	DISAEZT5	Strong	SusceptibilityMutation	[6]
Kidney cancer	DISBIPKM	Strong	Posttranslational Modification	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Psoriasis	DIS59VMN	Strong	Biomarker	[9]
Renal carcinoma	DISER9XT	Strong	Posttranslational Modification	[7]
Thyroid cancer	DIS3VLDH	Strong	Genetic Variation	[10]
Thyroid gland carcinoma	DISMNGZ0	Strong	Genetic Variation	[10]
Thyroid tumor	DISLVKMD	Strong	Genetic Variation	[10]
Endometrial carcinoma	DISXR5CY	moderate	Genetic Variation	[5]
Sarcoma	DISZDG3U	moderate	Genetic Variation	[11]
Soft tissue sarcoma	DISSN8XB	moderate	Genetic Variation	[11]
Cowden disease	DISMYKCE	Supportive	Autosomal dominant	[7]
Prostate cancer	DISF190Y	Limited	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[1]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[12]
Cowden syndrome 4	DISF2O2O	No Known	Unknown	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Killin (KLLN).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Killin (KLLN).	[15]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Killin (KLLN).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Killin (KLLN).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Killin (KLLN).	[18]

References

• [1] Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation.J Clin Endocrinol Metab. 2013 Mar;98(3):E586-94. doi: 10.1210/jc.2012-3490. Epub 2013 Feb 5.
• [2] Cancer-predisposition gene KLLN maintains pericentric H3K9 trimethylation protecting genomic stability.Nucleic Acids Res. 2016 May 5;44(8):3586-94. doi: 10.1093/nar/gkv1481. Epub 2015 Dec 15.
• [3] Role of DNA methylation in renal cell carcinoma.J Hematol Oncol. 2015 Jul 22;8:88. doi: 10.1186/s13045-015-0180-y.
• [4] Significant role and mechanism of microRNA-143-3p/KLLN axis in the development of coronary heart disease.Am J Transl Res. 2019 Jun 15;11(6):3610-3619. eCollection 2019.
• [5] Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study.Cancer. 2015 Mar 1;121(5):688-96. doi: 10.1002/cncr.29106. Epub 2014 Nov 5.
• [6] Susceptibility to childhood-onset rheumatoid arthritis: investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci.Arthritis Rheum. 2013 Jun;65(6):1663-7. doi: 10.1002/art.37913.
• [7] Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA. 2010 Dec 22;304(24):2724-31. doi: 10.1001/jama.2010.1877.
• [8] LINC00472 Acts as a Tumor Suppressor in NSCLC through KLLN-Mediated p53-Signaling Pathway via MicroRNA-149-3p and MicroRNA-4270.Mol Ther Nucleic Acids. 2019 Sep 6;17:563-577. doi: 10.1016/j.omtn.2019.06.003. Epub 2019 Jun 15.
• [9] MiR-744-3p regulates keratinocyte proliferation and differentiation via targeting KLLN in psoriasis.Exp Dermatol. 2019 Mar;28(3):283-291. doi: 10.1111/exd.13888.
• [10] KLLN epigenotype-phenotype associations in Cowden syndrome.Eur J Hum Genet. 2015 Nov;23(11):1538-43. doi: 10.1038/ejhg.2015.8. Epub 2015 Feb 11.
• [11] Alveolar rhabdomyosarcoma in an adolescent male patient - case report and current perspectives.Rom J Morphol Embryol. 2018;59(4):1247-1252.
• [12] Germline and somatic DNA methylation and epigenetic regulation of KILLIN in renal cell carcinoma.Genes Chromosomes Cancer. 2011 Aug;50(8):654-61. doi: 10.1002/gcc.20887. Epub 2011 May 16.
• [13] 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.
• [14] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.