Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWBXZ0E)

• DOT Name: DDB1- and CUL4-associated factor 15 (DCAF15)
• Gene Name: DCAF15
• Related Disease:
  Advanced cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Stomach cancer
  Colorectal carcinoma
  Plasma cell myeloma
• UniProt ID: DCA15_HUMAN
• PDB ID: 6PAI; 6Q0R; 6Q0V; 6Q0W; 6SJ7; 6UD7; 6UE5
• Pfam ID: PF14939
• Sequence:
  MAPSSKSERNSGAGSGGGGPGGAGGKRAAGRRREHVLKQLERVKISGQLSPRLFRKLPPR
  VCVSLKNIVDEDFLYAGHIFLGFSKCGRYVLSYTSSSGDDDFSFYIYHLYWWEFNVHSKL
  KLVRQVRLFQDEEIYSDLYLTVCEWPSDASKVIVFGFNTRSANGMLMNMMMMSDENHRDI
  YVSTVAVPPPGRCAACQDASRAHPGDPNAQCLRHGFMLHTKYQVVYPFPTFQPAFQLKKD
  QVVLLNTSYSLVACAVSVHSAGDRSFCQILYDHSTCPLAPASPPEPQSPELPPALPSFCP
  EAAPARSSGSPEPSPAIAKAKEFVADIFRRAKEAKGGVPEEARPALCPGPSGSRCRAHSE
  PLALCGETAPRDSPPASEAPASEPGYVNYTKLYYVLESGEGTEPEDELEDDKISLPFVVT
  DLRGRNLRPMRERTAVQGQYLTVEQLTLDFEYVINEVIRHDATWGHQFCSFSDYDIVILE
  VCPETNQVLINIGLLLLAFPSPTEEGQLRPKTYHTSLKVAWDLNTGIFETVSVGDLTEVK
  GQTSGSVWSSYRKSCVDMVMKWLVPESSGRYVNRMTNEALHKGCSLKVLADSERYTWIVL
• Function: Substrate-recognition component of the DCX(DCAF15) complex, a cullin-4-RING E3 ubiquitin-protein ligase complex that mediates ubiquitination and degradation of target proteins. The DCX(DCAF15) complex acts as a regulator of the natural killer (NK) cells effector functions, possibly by mediating ubiquitination and degradation of cohesin subunits SMC1A and SMC3. May play a role in the activation of antigen-presenting cells (APC) and their interaction with NK cells ; Binding of aryl sulfonamide anticancer drugs, such as indisulam (E7070) or E7820, change the substrate specificity of the DCX(DCAF15) complex, leading to promote ubiquitination and degradation of splicing factor RBM39. RBM39 degradation results in splicing defects and death in cancer cell lines. Aryl sulfonamide anticancer drugs change the substrate specificity of DCAF15 by acting as a molecular glue that promotes binding between DCAF15 and weak affinity interactor RBM39. Aryl sulfonamide anticancer drugs also promote ubiquitination and degradation of RBM23 and PRPF39.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[3]

4 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 DDB1- and CUL4-associated factor 15 (DCAF15).	[4]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of DDB1- and CUL4-associated factor 15 (DCAF15).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of DDB1- and CUL4-associated factor 15 (DCAF15).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DDB1- and CUL4-associated factor 15 (DCAF15).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DDB1- and CUL4-associated factor 15 (DCAF15).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DDB1- and CUL4-associated factor 15 (DCAF15).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DDB1- and CUL4-associated factor 15 (DCAF15).	[10]

References

• [1] Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.Cancer. 2018 Jul 1;124(13):2758-2765. doi: 10.1002/cncr.31398. Epub 2018 Apr 16.
• [2] Identification of specific and common diagnostic antibody markers for gastrointestinal cancers by SEREX screening using testis cDNA phage library.Oncotarget. 2018 Jan 1;9(26):18559-18569. doi: 10.18632/oncotarget.24963. eCollection 2018 Apr 6.
• [3] The emerging role for Cullin 4 family of E3 ligases in tumorigenesis.Biochim Biophys Acta Rev Cancer. 2019 Jan;1871(1):138-159. doi: 10.1016/j.bbcan.2018.11.007. Epub 2018 Dec 30.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.