Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8G2MX)

• DOT Name: Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC)
• Synonyms: Integral membrane protein CII-3; QPs-1; QPs1; Succinate dehydrogenase complex subunit C; Succinate-ubiquinone oxidoreductase cytochrome B large subunit; CYBL
• Gene Name: SDHC
• Related Disease:
  Hereditary pheochromocytoma-paraganglioma
  Neoplasm
  Paragangliomas 3
  Adenoma
  Adrenal adenoma
  Bone osteosarcoma
  Carney complex
  Carney-Stratakis syndrome
  Coffin-Siris syndrome
  Colorectal carcinoma
  Gastric cancer
  Gastrointestinal stromal tumour
  Head and neck neoplasm
  Hepatitis C virus infection
  Hepatocellular carcinoma
  High blood pressure
  Medullary thyroid gland carcinoma
  Multiple endocrine neoplasia type 1
  Multiple endocrine neoplasia type 2A
  Neurofibromatosis type 1
  Non-small-cell lung cancer
  Osteosarcoma
  Paraganglioma
  Pheochromocytoma
  Primary hyperparathyroidism
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Stomach cancer
  Systemic sclerosis
  Von hippel-lindau disease
  Choriocarcinoma
  Metastatic malignant neoplasm
  Neuroblastoma
  Neurofibromatosis
  Renal cell carcinoma
  Small-cell lung cancer
  Cowden disease
  Hereditary neoplastic syndrome
  Lung cancer
  Lung carcinoma
  Neuroendocrine neoplasm
  Thyroid tumor
  Mitochondrial disease
• UniProt ID: C560_HUMAN
• PDB ID: 8GS8
• Pfam ID: PF01127
• Sequence:
  MAALLLRHVGRHCLRAHFSPQLCIRNAVPLGTTAKEEMERFWNKNIGSNRPLSPHITIYS
  WSLPMAMSICHRGTGIALSAGVSLFGMSALLLPGNFESYLELVKSLCLGPALIHTAKFAL
  VFPLMYHTWNGIRHLMWDLGKGLKIPQLYQSGVVVLVLTVLSSMGLAAM
• Function: Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Thermogenesis (hsa04714)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Citric acid cycle (TCA cycle) (R-HSA-71403)
  Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:HS07014-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Definitive	Autosomal dominant	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Paragangliomas 3	DISULFVV	Definitive	Autosomal dominant	[3]
Adenoma	DIS78ZEV	Strong	Posttranslational Modification	[4]
Adrenal adenoma	DISC2UN8	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Genetic Variation	[6]
Carney complex	DISVL3IP	Strong	Biomarker	[7]
Carney-Stratakis syndrome	DISP3P3F	Strong	Autosomal dominant	[8]
Coffin-Siris syndrome	DIS8L03H	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[10]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[11]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Autosomal dominant	[8]
Head and neck neoplasm	DIS1OB2G	Strong	Biomarker	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[15]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[16]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[5]
Multiple endocrine neoplasia type 2A	DIS7D3W2	Strong	Biomarker	[17]
Neurofibromatosis type 1	DIS53JH9	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[6]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[20]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[21]
Primary hyperparathyroidism	DISB4U1Q	Strong	Genetic Variation	[22]
Prostate cancer	DISF190Y	Strong	Biomarker	[23]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[23]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[24]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[11]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[25]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[24]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[26]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[2]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[27]
Neurofibromatosis	DIS5N2R6	moderate	Biomarker	[18]
Renal cell carcinoma	DISQZ2X8	Moderate	Autosomal dominant	[8]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[28]
Cowden disease	DISMYKCE	Supportive	Autosomal dominant	[29]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	Genetic Variation	[30]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[31]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[31]
Neuroendocrine neoplasm	DISNPLOO	Limited	Genetic Variation	[32]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[33]
Mitochondrial disease	DISKAHA3	No Known	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[37]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[38]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[39]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[40]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[41]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[42]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[43]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[44]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[45]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[46]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[49]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[50]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[51]

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 Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[47]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (SDHC).	[48]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.JAMA Oncol. 2016 Jul 1;2(7):922-8. doi: 10.1001/jamaoncol.2016.0256.
• [3] 15 YEARS OF PARAGANGLIOMA: Clinical manifestations of paraganglioma syndromes types 1-5. Endocr Relat Cancer. 2015 Aug;22(4):T91-103. doi: 10.1530/ERC-15-0268.
• [4] Epigenetic Mutation of the Succinate Dehydrogenase C Promoter in a Patient With Two Paragangliomas.J Clin Endocrinol Metab. 2016 Feb;101(2):359-63. doi: 10.1210/jc.2015-3856. Epub 2015 Dec 11.
• [5] Multiple endocrine neoplasias: advances and challenges for the future.J Intern Med. 2009 Jul;266(1):1-4. doi: 10.1111/j.1365-2796.2009.02108.x.
• [6] A 4.6 kb genomic duplication on 20p12.2-12.3 is associated with brachydactyly type A2 in a Chinese family.J Med Genet. 2011 May;48(5):312-6. doi: 10.1136/jmg.2010.084814. Epub 2011 Feb 26.
• [7] Recurrent epimutation of SDHC in gastrointestinal stromal tumors.Sci Transl Med. 2014 Dec 24;6(268):268ra177. doi: 10.1126/scitranslmed.3009961.
• [8] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [9] Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome.Mol Cell Endocrinol. 2018 Jul 5;469:107-111. doi: 10.1016/j.mce.2017.07.018. Epub 2017 Jul 21.
• [10] Genetic variations in genes of metabolic enzymes predict postoperational prognosis of patients with colorectal cancer.Mol Cancer. 2015 Sep 17;14:171. doi: 10.1186/s12943-015-0442-x.
• [11] No association of an SDHC gene polymorphism with gastric cancer.Asian Pac J Cancer Prev. 2006 Oct-Dec;7(4):525-8.
• [12] Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma.Horm Metab Res. 2009 Sep;41(9):672-5. doi: 10.1055/s-0029-1202814. Epub 2009 Apr 2.
• [13] Treatment of hepatitis C virus core-positive hepatocytes with the transfer of recombinant caspase-3 using the 2',5'-oligoadenylate synthetase gene promoter.Acta Biochim Biophys Sin (Shanghai). 2009 Jul;41(7):554-60. doi: 10.1093/abbs/gmp044.
• [14] SDHC-related deficiency of SDH complex activity promotes growth and metastasis of hepatocellular carcinoma via ROS/NFB signaling.Cancer Lett. 2019 Oct 1;461:44-55. doi: 10.1016/j.canlet.2019.07.001. Epub 2019 Jul 3.
• [15] Genetic screening for pheochromocytoma: should SDHC gene analysis be included?.J Med Genet. 2007 Sep;44(9):586-7. doi: 10.1136/jmg.2007.051045. Epub 2007 Jun 8.
• [16] No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma.Endocr Relat Cancer. 2005 Dec;12(4):1011-6. doi: 10.1677/erc.1.00996.
• [17] Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma. J Clin Endocrinol Metab. 2004 Nov;89(11):5694-9. doi: 10.1210/jc.2004-0769.
• [18] Genotype-phenotype correlation in paediatric pheochromocytoma and paraganglioma: a single centre experience from India.J Pediatr Endocrinol Metab. 2017 May 1;30(5):575-581. doi: 10.1515/jpem-2016-0375.
• [19] miR-150, p53 protein and relevant miRNAs consist of a regulatory network in NSCLC tumorigenesis.Oncol Rep. 2013 Jul;30(1):492-8. doi: 10.3892/or.2013.2453. Epub 2013 May 13.
• [20] The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes.Endocr Pathol. 2019 Mar;30(1):64-73. doi: 10.1007/s12022-018-9555-2.
• [21] Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association.Virchows Arch. 2015 Jun;466(6):727-32. doi: 10.1007/s00428-015-1755-2. Epub 2015 Mar 24.
• [22] AN AGGRESSIVE TEMPORAL BONE SDHC PARAGANGLIOMA ASSOCIATED WITH INCREASED HIF-2 SIGNALING.Endocr Pract. 2016 Feb;22(2):190-5. doi: 10.4158/EP15889.OR. Epub 2015 Oct 22.
• [23] Molecular cloning and characterization of human homeobox gene Nkx3.1 promoter.Acta Biochim Biophys Sin (Shanghai). 2004 Jan;36(1):64-7. doi: 10.1093/abbs/36.1.64.
• [24] Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3.Endocr Relat Cancer. 2012 May 3;19(3):283-90. doi: 10.1530/ERC-11-0324. Print 2012 Jun.
• [25] Contribution of single nucleotide polymorphisms of the IL1A gene to the cleavage of precursor IL-1alpha and its transcription activity.Immunogenetics. 2007 Jun;59(6):441-8. doi: 10.1007/s00251-007-0213-y. Epub 2007 Apr 18.
• [26] The modified firefly luciferase reporter gene (luc+) but not Renilla luciferase is induced by all-trans retinoic acid in MCF-7 breast cancer cells.Breast Cancer Res Treat. 2003 Mar;78(1):119-26. doi: 10.1023/a:1022179717847.
• [27] Neuronal cell lines transfected with the dopamine D2 receptor gene promoter as a model for studying the effects of antidepressant drugs.Brain Res Mol Brain Res. 2004 Sep 10;128(1):75-82. doi: 10.1016/j.molbrainres.2004.06.006.
• [28] Adenovirus-mediated suicide SCLC gene therapy using the increased activity of the hTERT promoter by the MMRE and SV40 enhancer.Biosci Biotechnol Biochem. 2005 Jan;69(1):56-62. doi: 10.1271/bbb.69.56.
• [29] Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet. 2012 Jan 15;21(2):300-10. doi: 10.1093/hmg/ddr459. Epub 2011 Oct 6.
• [30] Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.J Med Genet. 2018 Jun;55(6):384-394. doi: 10.1136/jmedgenet-2017-105127. Epub 2018 Jan 31.
• [31] Genetic Polymorphisms in the Apoptosis-Associated Gene CASP3 and the Risk of Lung Cancer in Chinese Population.PLoS One. 2016 Oct 10;11(10):e0164358. doi: 10.1371/journal.pone.0164358. eCollection 2016.
• [32] Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.Clin Cancer Res. 2010 Aug 15;16(16):4148-54. doi: 10.1158/1078-0432.CCR-10-0637. Epub 2010 Jun 30.
• [33] Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer.Endocr Relat Cancer. 2015 Apr;22(2):121-30. doi: 10.1530/ERC-14-0537.
• [34] 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.
• [35] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [36] 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.
• [37] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [38] 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.
• [39] 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.
• [40] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [41] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [42] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [43] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [44] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [45] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [46] 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.
• [47] 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.
• [48] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [49] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [50] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [51] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.