Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHMZZ0A)

• DOT Name: SIN3-HDAC complex-associated factor (SINHCAF)
• Synonyms: Protein FAM60A; Tera protein homolog
• Gene Name: SINHCAF
• Related Disease:
  Carcinoma of esophagus
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Non-insulin dependent diabetes
  Pancreatic cancer
  Stomach cancer
• UniProt ID: SHCAF_HUMAN
• Pfam ID: PF15396
• Sequence:
  MFGFHKPKMYRSIEGCCICRAKSSSSRFTDSKRYEKDFQSCFGLHETRSGDICNACVLLV
  KRWKKLPAGSKKNWNHVVDARAGPSLKTTLKPKKVKTLSGNRIKSNQISKLQKEFKRHNS
  DAHSTTSSASPAQSPCYSNQSDDGSDTEMASGSNRTPVFSFLDLTYWKRQKICCGIIYKG
  RFGEVLIDTHLFKPCCSNKKAAAEKPEEQGPEPLPISTQEW
• Function: Subunit of the Sin3 deacetylase complex (Sin3/HDAC), this subunit is important for the repression of genes encoding components of the TGF-beta signaling pathway. Core component of a SIN3A complex (composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1) present in embryonic stem (ES) cells. Promotes the stability of SIN3A and its presence on chromatin and is essential for maintaining the potential of ES cells to proliferate rapidly, while ensuring a short G1-phase of the cell cycle, thereby preventing premature lineage priming.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[11]
ACYLINE	DM9GRTK	Phase 2	ACYLINE increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[15]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of SIN3-HDAC complex-associated factor (SINHCAF).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of SIN3-HDAC complex-associated factor (SINHCAF).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SIN3-HDAC complex-associated factor (SINHCAF).	[17]

References

• [1] Integrative analysis of copy number and transcriptional expression profiles in esophageal cancer to identify a novel driver gene for therapy.Sci Rep. 2017 Feb 7;7:42060. doi: 10.1038/srep42060.
• [2] FAM60A, increased by Helicobacter pylori, promotes proliferation and suppresses apoptosis of gastric cancer cells by targeting the PI3K/AKT pathway.Biochem Biophys Res Commun. 2020 Jan 22;521(4):1003-1009. doi: 10.1016/j.bbrc.2019.11.029. Epub 2019 Nov 12.
• [3] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] 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.
• [12] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.