Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT89XFPN)

• DOT Name: Forkhead box protein L1 (FOXL1)
• Synonyms: Forkhead-related protein FKHL11; Forkhead-related transcription factor 7; FREAC-7
• Gene Name: FOXL1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Depression
  Glioma
  Hypoplastic left heart syndrome
  Neoplasm
  Advanced cancer
  Bone osteosarcoma
  Matthew-Wood syndrome
  Osteosarcoma
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Congenital heart disease
  Gallbladder cancer
  Gallbladder carcinoma
• UniProt ID: FOXL1_HUMAN
• Pfam ID: PF00250
• Sequence:
  MSHLFDPRLPALAASPMLYLYGPERPGLPLAFAPAAALAASGRAETPQKPPYSYIALIAM
  AIQDAPEQRVTLNGIYQFIMDRFPFYHDNRQGWQNSIRHNLSLNDCFVKVPREKGRPGKG
  SYWTLDPRCLDMFENGNYRRRKRKPKPGPGAPEAKRPRAETHQRSAEAQPEAGSGAGGSG
  PAISRLQAAPAGPSPLLDGPSPPAPLHWPGTASPNEDAGDAAQGAAAVAVGQAARTGDGP
  GSPLRPASRSSPKSSDKSKSFSIDSILAGKQGQKPPSGDELLGGAKPGPGGRLGASLLAA
  SSSLRPPFNASLMLDPHVQGGFYQLGIPFLSYFPLQVPDTVLHFQ
• Function: Transcription factor required for proper proliferation and differentiation in the gastrointestinal epithelium. Target gene of the hedgehog (Hh) signaling pathway via GLI2 and GLI3 transcription factors.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Hypoplastic left heart syndrome	DISSLFZ4	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[7]
Matthew-Wood syndrome	DISA7HR7	moderate	Altered Expression	[8]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[7]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[8]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[8]
Congenital heart disease	DISQBA23	Disputed	Autosomal dominant	[9]
Gallbladder cancer	DISXJUAF	Limited	Altered Expression	[10]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[10]

3 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 Forkhead box protein L1 (FOXL1).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Forkhead box protein L1 (FOXL1).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Forkhead box protein L1 (FOXL1).	[14]

1 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 decreases the methylation of Forkhead box protein L1 (FOXL1).	[13]

References

• [1] Overexpression of Forkhead Box L1 (FOXL1) Inhibits the Proliferation and Invasion of Breast Cancer Cells.Oncol Res. 2017 Jul 5;25(6):959-965. doi: 10.3727/096504016X14803482769179. Epub 2016 Nov 29.
• [2] A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer.Sci Rep. 2015 May 20;5:10442. doi: 10.1038/srep10442.
• [3] Long noncoding RNA EPB41L4A-AS2 inhibits hepatocellular carcinoma development by sponging miR-301a-5p and targeting FOXL1.J Exp Clin Cancer Res. 2019 Apr 10;38(1):153. doi: 10.1186/s13046-019-1128-9.
• [4] FOXL1 overexpression is associated with poor outcome in patients with glioma.Oncol Lett. 2019 Jul;18(1):751-757. doi: 10.3892/ol.2019.10351. Epub 2019 May 13.
• [5] Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009 Jun;84(6):780-91. doi: 10.1016/j.ajhg.2009.05.005. Epub 2009 Jun 4.
• [6] Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing ofDistinct Tumor Suppressor Genes.Stem Cell Reports. 2017 Sep 12;9(3):956-971. doi: 10.1016/j.stemcr.2017.08.001. Epub 2017 Aug 31.
• [7] Inhibitory effects of forkhead box L1 gene on osteosarcoma growth through the induction of cell cycle arrest and apoptosis.Oncol Rep. 2015 Jul;34(1):265-71. doi: 10.3892/or.2015.3969. Epub 2015 May 11.
• [8] FOXL1, a novel candidate tumor suppressor, inhibits tumor aggressiveness and predicts outcome in human pancreatic cancer.Cancer Res. 2013 Sep 1;73(17):5416-25. doi: 10.1158/0008-5472.CAN-13-0362. Epub 2013 Jun 25.
• [9] 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.
• [10] Forkhead box L1 is frequently downregulated in gallbladder cancer and inhibits cell growth through apoptosis induction by mitochondrial dysfunction.PLoS One. 2014 Jul 10;9(7):e102084. doi: 10.1371/journal.pone.0102084. eCollection 2014.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] 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.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.