Details of Drug Off-Target (DOT)

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

• DOT Name: MHC class II regulatory factor RFX1 (RFX1)
• Synonyms: Enhancer factor C; EF-C; Regulatory factor X 1; RFX; Transcription factor RFX1
• Gene Name: RFX1
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Glioma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Bardet biedl syndrome
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Neoplasm
  Schizophrenia
  Sensorineural hearing loss disorder
  Lupus
  MHC class II deficiency
  Systemic lupus erythematosus
  Coronary atherosclerosis
  Coronary heart disease
  Adenocarcinoma
  Autoimmune disease
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Medulloblastoma
  Multiple sclerosis
  Nervous system inflammation
  Neuroblastoma
• UniProt ID: RFX1_HUMAN
• PDB ID: 1DP7
• Pfam ID: PF04589 ; PF02257
• Sequence:
  MATQAYTELQAAPPPSQPPQAPPQAQPQPPPPPPPAAPQPPQPPTAAATPQPQYVTELQS
  PQPQAQPPGGQKQYVTELPAVPAPSQPTGAPTPSPAPQQYIVVTVSEGAMRASETVSEAS
  PGSTASQTGVPTQVVQQVQGTQQRLLVQTSVQAKPGHVSPLQLTNIQVPQQALPTQRLVV
  QSAAPGSKGGQVSLTVHGTQQVHSPPEQSPVQANSSSSKTAGAPTGTVPQQLQVHGVQQS
  VPVTQERSVVQATPQAPKPGPVQPLTVQGLQPVHVAQEVQQLQQVPVPHVYSSQVQYVEG
  GDASYTASAIRSSTYSYPETPLYTQTASTSYYEAAGTATQVSTPATSQAVASSGSMPMYV
  SGSQVVASSTSTGAGASNSSGGGGSGGGGGGGGGGGGGGSGSTGGGGSGAGTYVIQGGYM
  LGSASQSYSHTTRASPATVQWLLDNYETAEGVSLPRSTLYCHYLLHCQEQKLEPVNAASF
  GKLIRSVFMGLRTRRLGTRGNSKYHYYGLRIKASSPLLRLMEDQQHMAMRGQPFSQKQRL
  KPIQKMEGMTNGVAVGQQPSTGLSDISAQVQQYQQFLDASRSLPDFTELDLQGKVLPEGV
  GPGDIKAFQVLYREHCEAIVDVMVNLQFTLVETLWKTFWRYNLSQPSEAPPLAVHDEAEK
  RLPKAILVLLSKFEPVLQWTKHCDNVLYQGLVEILIPDVLRPIPSALTQAIRNFAKSLES
  WLTHAMVNIPEEMLRVKVAAAGAFAQTLRRYTSLNHLAQAARAVLQNTAQINQMLSDLNR
  VDFANVQEQASWVCRCEDRVVQRLEQDFKVTLQQQNSLEQWAAWLDGVVSQVLKPYQGSA
  GFPKAAKLFLLKWSFYSSMVIRDLTLRSAASFGSFHLIRLLYDEYMYYLIEHRVAQAKGE
  TPIAVMGEFANLATSLNPLDPDKDEEEEEEEESEDELPQDISLAAGGESPALGPETLEPP
  AKLARTDARGLFVQALPSS
• Function: Regulatory factor essential for MHC class II genes expression. Binds to the X boxes of MHC class II genes. Also binds to an inverted repeat (ENH1) required for hepatitis B virus genes expression and to the most upstream element (alpha) of the RPL30 promoter.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[4]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[4]
Bardet biedl syndrome	DISTBNZW	Strong	Altered Expression	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[9]
Lupus	DISOKJWA	moderate	Biomarker	[10]
MHC class II deficiency	DISWMI0G	moderate	Genetic Variation	[11]
Systemic lupus erythematosus	DISI1SZ7	moderate	Altered Expression	[12]
Coronary atherosclerosis	DISKNDYU	Disputed	Altered Expression	[13]
Coronary heart disease	DIS5OIP1	Disputed	Altered Expression	[13]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[14]
Autoimmune disease	DISORMTM	Limited	Biomarker	[12]
Barrett esophagus	DIS416Y7	Limited	Altered Expression	[14]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[15]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[15]
Medulloblastoma	DISZD2ZL	Limited	Altered Expression	[16]
Multiple sclerosis	DISB2WZI	Limited	Altered Expression	[17]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[12]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of MHC class II regulatory factor RFX1 (RFX1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of MHC class II regulatory factor RFX1 (RFX1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MHC class II regulatory factor RFX1 (RFX1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of MHC class II regulatory factor RFX1 (RFX1).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of MHC class II regulatory factor RFX1 (RFX1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of MHC class II regulatory factor RFX1 (RFX1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MHC class II regulatory factor RFX1 (RFX1).	[23]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of MHC class II regulatory factor RFX1 (RFX1).	[25]

References

• [1] Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma.Neuro Oncol. 2014 Aug;16(8):1078-85. doi: 10.1093/neuonc/nou010. Epub 2014 Feb 12.
• [2] Identification of an epigenetically silenced gene, RFX1, in human glioma cells using restriction landmark genomic scanning.Oncogene. 2004 Oct 14;23(47):7772-9. doi: 10.1038/sj.onc.1208058.
• [3] Downregulation of RFX1 predicts poor prognosis of patients with small hepatocellular carcinoma.Eur J Surg Oncol. 2018 Jul;44(7):1087-1093. doi: 10.1016/j.ejso.2018.04.017. Epub 2018 Apr 27.
• [4] Regulatory Factor X1 Downregulation Contributes to Monocyte Chemoattractant Protein-1 Overexpression in CD14+ Monocytes via Epigenetic Mechanisms in Coronary Heart Disease.Front Genet. 2019 Nov 1;10:1098. doi: 10.3389/fgene.2019.01098. eCollection 2019.
• [5] Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.Nature. 2003 Oct 9;425(6958):628-33. doi: 10.1038/nature02030. Epub 2003 Sep 21.
• [6] Interactions of the transcription factors MIBP1 and RFX1 with the EP element of the hepatitis B virus enhancer.J Virol. 1996 Sep;70(9):6060-6. doi: 10.1128/JVI.70.9.6060-6066.1996.
• [7] Integrative genomic analyses of a novel cytokine, interleukin-34 and its potential role in cancer prediction.Int J Mol Med. 2015 Jan;35(1):92-102. doi: 10.3892/ijmm.2014.2001. Epub 2014 Nov 12.
• [8] Putative Astroglial Dysfunction in Schizophrenia: A Meta-Analysis of (1)H-MRS Studies of Medial Prefrontal Myo-Inositol.Front Psychiatry. 2018 Sep 21;9:438. doi: 10.3389/fpsyt.2018.00438. eCollection 2018.
• [9] ATOH1/RFX1/RFX3 transcription factors facilitate the differentiation and characterisation of inner ear hair cell-like cells from patient-specific induced pluripotent stem cells harbouring A8344G mutation of mitochondrial DNA.Cell Death Dis. 2018 Apr 1;9(4):437. doi: 10.1038/s41419-018-0488-y.
• [10] Impaired DNA methylation and its mechanisms in CD4(+)T cells of systemic lupus erythematosus.J Autoimmun. 2013 Mar;41:92-9. doi: 10.1016/j.jaut.2013.01.005. Epub 2013 Jan 20.
• [11] The RFX complex is crucial for the constitutive and CIITA-mediated transactivation of MHC class I and beta2-microglobulin genes.Immunity. 1998 Oct;9(4):531-41. doi: 10.1016/s1074-7613(00)80636-6.
• [12] IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation.Nat Commun. 2018 Feb 8;9(1):583. doi: 10.1038/s41467-018-02890-0.
• [13] RFX1 downregulation contributes to TLR4 overexpression in CD14(+) monocytes via epigenetic mechanisms in coronary artery disease.Clin Epigenetics. 2019 Mar 11;11(1):44. doi: 10.1186/s13148-019-0646-9.
• [14] Study of FoxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development.PLoS Genet. 2011 Sep;7(9):e1002277. doi: 10.1371/journal.pgen.1002277. Epub 2011 Sep 15.
• [15] Expression of regulatory factor X1 can predict the prognosis of breast cancer.Oncol Lett. 2017 Jun;13(6):4334-4340. doi: 10.3892/ol.2017.6005. Epub 2017 Apr 7.
• [16] Regulatory factor X1-induced down-regulation of transforming growth factor 2 transcription in human neuroblastoma cells.J Biol Chem. 2012 Jun 29;287(27):22730-9. doi: 10.1074/jbc.M111.338590. Epub 2012 May 11.
• [17] Upregulation of transcription factors controlling MHC expression in multiple sclerosis lesions.Glia. 2001 Oct;36(1):68-77. doi: 10.1002/glia.1096.
• [18] 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.
• [19] The ATRA-dependent overexpression of the glutamate transporter EAAC1 requires RARbeta induction. Biochim Biophys Acta. 2009 Sep;1788(9):1861-8. doi: 10.1016/j.bbamem.2009.05.005. Epub 2009 May 18.
• [20] 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.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [25] Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.