Details of Drug Off-Target (DOT)

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

• DOT Name: HERV-H LTR-associating protein 2 (HHLA2)
• Synonyms: Human endogenous retrovirus-H long terminal repeat-associating protein 2
• Gene Name: HHLA2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Matthew-Wood syndrome
  Advanced cancer
  Clear cell renal carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Gastric cancer
  Glioma
  Intrahepatic cholangiocarcinoma
  Malignant glioma
  Neoplasm
  Pancreatic ductal carcinoma
  Polyarteritis nodosa
  Stomach cancer
  Vasculitis due to ADA2 deficiency
  Bladder transitional cell carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Esophageal cancer
  Liver cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Squamous cell carcinoma
• UniProt ID: HHLA2_HUMAN
• Pfam ID: PF07654 ; PF07686
• Sequence:
  MKAQTALSFFLILITSLSGSQGIFPLAFFIYVPMNEQIVIGRLDEDIILPSSFERGSEVV
  IHWKYQDSYKVHSYYKGSDHLESQDPRYANRTSLFYNEIQNGNASLFFRRVSLLDEGIYT
  CYVGTAIQVITNKVVLKVGVFLTPVMKYEKRNTNSFLICSVLSVYPRPIITWKMDNTPIS
  ENNMEETGSLDSFSINSPLNITGSNSSYECTIENSLLKQTWTGRWTMKDGLHKMQSEHVS
  LSCQPVNDYFSPNQDFKVTWSRMKSGTFSVLAYYLSSSQNTIINESRFSWNKELINQSDF
  SMNLMDLNLSDSGEYLCNISSDEYTLLTIHTVHVEPSQETASHNKGLWILVPSAILAAFL
  LIWSVKCCRAQLEARRSRHPADGAQQERCCVPPGERCPSAPDNGEENVPLSGKV
• Function: Through interaction with TMIGD2, costimulates T-cells in the context of TCR-mediated activation. Enhances T-cell proliferation and cytokine production via an AKT-dependent signaling cascade.
• Tissue Specificity: Expressed at high levels in colon, kidney, testis, lung and pancreas, and at lower levels in small intestine, liver and skeletal muscle. In immune cells, highly expressed in B-cells, dendritic cells and macrophages. Not detected in T-cells.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[8]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Biomarker	[9]
Polyarteritis nodosa	DISRQ5X8	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Vasculitis due to ADA2 deficiency	DIS1UHPY	Strong	Biomarker	[5]
Bladder transitional cell carcinoma	DISNL46A	Limited	Altered Expression	[10]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[11]
Esophageal cancer	DISGB2VN	Limited	Biomarker	[11]
Liver cancer	DISDE4BI	Limited	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[12]
Lung cancer	DISCM4YA	Limited	Biomarker	[12]
Lung carcinoma	DISTR26C	Limited	Biomarker	[12]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[10]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[13]
Pancreatic cancer	DISJC981	Limited	Biomarker	[9]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[14]

2 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 HERV-H LTR-associating protein 2 (HHLA2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of HERV-H LTR-associating protein 2 (HHLA2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of HERV-H LTR-associating protein 2 (HHLA2).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of HERV-H LTR-associating protein 2 (HHLA2).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of HERV-H LTR-associating protein 2 (HHLA2).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of HERV-H LTR-associating protein 2 (HHLA2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of HERV-H LTR-associating protein 2 (HHLA2).	[21]

References

• [1] Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein.Clin Cancer Res. 2015 May 15;21(10):2359-66. doi: 10.1158/1078-0432.CCR-14-1495. Epub 2014 Dec 30.
• [2] B7-H5/CD28H is a co-stimulatory pathway and correlates with improved prognosis in pancreatic ductal adenocarcinoma.Cancer Sci. 2019 Feb;110(2):530-539. doi: 10.1111/cas.13914. Epub 2019 Jan 16.
• [3] Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients.Cancer Cell Int. 2019 Apr 16;19:101. doi: 10.1186/s12935-019-0813-2. eCollection 2019.
• [4] Overexpression of HHLA2, a member of the B7 family, is associated with worse survival in human colorectal carcinoma.Onco Targets Ther. 2018 Mar 20;11:1563-1570. doi: 10.2147/OTT.S160493. eCollection 2018.
• [5] Prognostic Significance of Potential Immune Checkpoint Member HHLA2 in Human Tumors: A Comprehensive Analysis.Front Immunol. 2019 Jul 15;10:1573. doi: 10.3389/fimmu.2019.01573. eCollection 2019.
• [6] HHLA2 overexpression is a novel biomarker of malignant status and poor prognosis in gastric cancer.Hum Cell. 2020 Jan;33(1):116-122. doi: 10.1007/s13577-019-00280-2. Epub 2019 Sep 24.
• [7] HHLA2 is a novel prognostic predictor and potential therapeutic target in malignant glioma.Oncol Rep. 2019 Dec;42(6):2309-2322. doi: 10.3892/or.2019.7343. Epub 2019 Oct 1.
• [8] HHLA2 in intrahepatic cholangiocarcinoma: an immune checkpoint with prognostic significance and wider expression compared with PD-L1.J Immunother Cancer. 2019 Mar 18;7(1):77. doi: 10.1186/s40425-019-0554-8.
• [9] HHLA2 is a novel immune checkpoint protein in pancreatic ductal adenocarcinoma and predicts post-surgical survival.Cancer Lett. 2019 Feb 1;442:333-340. doi: 10.1016/j.canlet.2018.11.007. Epub 2018 Nov 14.
• [10] Immune Checkpoint Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 is Upregulated and Independently Predicts Unfavorable Prognosis in Bladder Urothelial Carcinoma.Nephron. 2019;141(4):256-264. doi: 10.1159/000495887. Epub 2019 Jan 2.
• [11] Comprehensive molecular profiling of the B7 family in gastrointestinal cancer.Cell Prolif. 2018 Oct;51(5):e12468. doi: 10.1111/cpr.12468. Epub 2018 Jul 12.
• [12] HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status.Clin Cancer Res. 2017 Feb 1;23(3):825-832. doi: 10.1158/1078-0432.CCR-15-3071. Epub 2016 Aug 23.
• [13] Wide Expression and Significance of Alternative Immune Checkpoint Molecules, B7x and HHLA2, in PD-L1-Negative Human Lung Cancers.Clin Cancer Res. 2018 Apr 15;24(8):1954-1964. doi: 10.1158/1078-0432.CCR-17-2924. Epub 2018 Jan 26.
• [14] The Expression Patterns and Associated Clinical Parameters of Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 and Transmembrane and Immunoglobulin Domain Containing 2 in Oral Squamous Cell Carcinoma.Dis Markers. 2019 Apr 7;2019:5421985. doi: 10.1155/2019/5421985. eCollection 2019.
• [15] 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.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [18] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [21] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.