Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZTZ4RD)

• DOT Name: LETM1 domain-containing protein 1 (LETMD1)
• Synonyms: Cervical cancer 1 proto-oncogene protein p40; Cervical cancer proto-oncogene 2 protein; HCCR-1; HCRR-2
• Gene Name: LETMD1
• Related Disease:
  Breast carcinoma
  Breast neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Liver cancer
  Advanced cancer
  Breast cancer
  leukaemia
  Leukemia
  Acute leukaemia
  Gastric cancer
  Glioma
  Neoplasm
  Stomach cancer
• UniProt ID: LTMD1_HUMAN
• Pfam ID: PF07766
• Sequence:
  MALSRVCWARSAVWGSAVTPGHFVTRRLQLGRSGLAWGAPRSSKLHLSPKADVKNLMSYV
  VTKTKAINGKYHRFLGRHFPRFYVLYTIFMKGLQMLWADAKKARRIKTNMWKHNIKFHQL
  PYREMEHLRQFRQDVTKCLFLGIISIPPFANYLVFLLMYLFPRQLLIRHFWTPKQQTDFL
  DIYHAFRKQSHPEIISYLEKVIPLISDAGLRWRLTDLCTKIQRGTHPAIHDILALRECFS
  NHPLGMNQLQALHVKALSRAMLLTSYLPPPLLRHRLKTHTTVIHQLDKALAKLGIGQLTA
  QEVKSACYLRGLNSTHIGEDRCRTWLGEWLQISCSLKEAELSLLLHNVVLLSTNYLGTRR
• Function: Plays an essential role for mitochondrial structure and function, as well as thermogenesis of brown adipocytes. In brown adipose tissue also localizes in the nucleus where it interacts with the chromatin remodeler SMARCA4 to regulate thermogenic genes expression, such as UCP1. May regulate phagocytosis and inflammatory responses to lipopolysaccharide in macrophages. Involved in tumorigenesis and may function as a negative regulator of the p53/TP53.
• Tissue Specificity: Kidney, liver, skeletal muscle, heart and brain. Overexpressed in various tumors including leukemia, lymphoma, and carcinomas of the breast, kidney, ovary, stomach, colon and uterine cervix.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Liver cancer	DISDE4BI	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Breast cancer	DIS7DPX1	moderate	Biomarker	[1]
leukaemia	DISS7D1V	moderate	Biomarker	[7]
Leukemia	DISNAKFL	moderate	Biomarker	[7]
Acute leukaemia	DISDQFDI	Disputed	Biomarker	[7]
Gastric cancer	DISXGOUK	Limited	Biomarker	[8]
Glioma	DIS5RPEH	Limited	Altered Expression	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]
Stomach cancer	DISKIJSX	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of LETM1 domain-containing protein 1 (LETMD1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of LETM1 domain-containing protein 1 (LETMD1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of LETM1 domain-containing protein 1 (LETMD1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of LETM1 domain-containing protein 1 (LETMD1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of LETM1 domain-containing protein 1 (LETMD1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of LETM1 domain-containing protein 1 (LETMD1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of LETM1 domain-containing protein 1 (LETMD1).	[14]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of LETM1 domain-containing protein 1 (LETMD1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of LETM1 domain-containing protein 1 (LETMD1).	[17]

References

• [1] Interaction of HCCR-1 and Bax in breast cancer.J BUON. 2019 May-Jun;24(3):1027-1037.
• [2] The HCCR oncoprotein as a biomarker for human breast cancer.Clin Cancer Res. 2005 Nov 1;11(21):7700-8. doi: 10.1158/1078-0432.CCR-04-2609.
• [3] Silencing of the HCCR2 gene induces apoptosis and suppresses the aggressive phenotype of hepatocellular carcinoma cells in culture.J Gastrointest Surg. 2011 Oct;15(10):1807-13. doi: 10.1007/s11605-011-1633-4. Epub 2011 Jul 28.
• [4] Calcitriol Inhibits Cervical Cancer Cell Proliferation Through Downregulation of HCCR1 Expression.Oncol Res. 2014;22(5-6):301-9. doi: 10.3727/096504015X14424348425991.
• [5] Clinical implication of elevated human cervical cancer oncogene-1 expression in esophageal squamous cell carcinoma.J Histochem Cytochem. 2012 Jul;60(7):512-20. doi: 10.1369/0022155412444437. Epub 2012 Apr 17.
• [6] Targeting HCCR expression resensitizes gastric cancer cells to chemotherapy via down-regulating the activation of STAT3.Sci Rep. 2016 Apr 7;6:24196. doi: 10.1038/srep24196.
• [7] Quantitative detection of the human cervical cancer oncogene for monitoring the minimal residual disease in acute leukemia.Exp Biol Med (Maywood). 2015 Jan;240(1):128-34. doi: 10.1177/1535370214543067. Epub 2014 Jul 17.
• [8] HCCR-1 is a Novel Prognostic Indicator for Gastric Cancer and Promotes Cell Proliferation.J Cancer. 2019 Jun 9;10(15):3533-3542. doi: 10.7150/jca.22462. eCollection 2019.
• [9] Isolation of novel differentially expressed genes related to human glioma using cDNA microarray and characterizations of two novel full-length genes.J Neurooncol. 2002 Feb;56(3):197-208. doi: 10.1023/a:1015079705841.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] 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.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [16] 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.
• [17] 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.
• [18] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.