Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCRR1M9)

• DOT Name: Calcium-activated chloride channel regulator 4 (CLCA4)
• Synonyms: EC 3.4.-.-; Calcium-activated chloride channel family member 4; hCLCA4; Calcium-activated chloride channel protein 2; CaCC-2; hCaCC-2; Chloride channel accessory 4
• Gene Name: CLCA4
• Related Disease:
  Hepatic encephalopathy
  Advanced cancer
  Bladder cancer
  Male infertility
  Neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Cystic fibrosis
  Hepatocellular carcinoma
• UniProt ID: CLCA4_HUMAN
• EC Number: 3.4.-.-
• Pfam ID: PF08434 ; PF00092
• Sequence:
  MGLFRGFVFLLVLCLLHQSNTSFIKLNNNGFEDIVIVIDPSVPEDEKIIEQIEDMVTTAS
  TYLFEATEKRFFFKNVSILIPENWKENPQYKRPKHENHKHADVIVAPPTLPGRDEPYTKQ
  FTECGEKGEYIHFTPDLLLGKKQNEYGPPGKLFVHEWAHLRWGVFDEYNEDQPFYRAKSK
  KIEATRCSAGISGRNRVYKCQGGSCLSRACRIDSTTKLYGKDCQFFPDKVQTEKASIMFM
  QSIDSVVEFCNEKTHNQEAPSLQNIKCNFRSTWEVISNSEDFKNTIPMVTPPPPPVFSLL
  KISQRIVCLVLDKSGSMGGKDRLNRMNQAAKHFLLQTVENGSWVGMVHFDSTATIVNKLI
  QIKSSDERNTLMAGLPTYPLGGTSICSGIKYAFQVIGELHSQLDGSEVLLLTDGEDNTAS
  SCIDEVKQSGAIVHFIALGRAADEAVIEMSKITGGSHFYVSDEAQNNGLIDAFGALTSGN
  TDLSQKSLQLESKGLTLNSNAWMNDTVIIDSTVGKDTFFLITWNSLPPSISLWDPSGTIM
  ENFTVDATSKMAYLSIPGTAKVGTWAYNLQAKANPETLTITVTSRAANSSVPPITVNAKM
  NKDVNSFPSPMIVYAEILQGYVPVLGANVTAFIESQNGHTEVLELLDNGAGADSFKNDGV
  YSRYFTAYTENGRYSLKVRAHGGANTARLKLRPPLNRAAYIPGWVVNGEIEANPPRPEID
  EDTQTTLEDFSRTASGGAFVVSQVPSLPLPDQYPPSQITDLDATVHEDKIILTWTAPGDN
  FDVGKVQRYIIRISASILDLRDSFDDALQVNTTDLSPKEANSKESFAFKPENISEENATH
  IFIAIKSIDKSNLTSKVSNIAQVTLFIPQANPDDIDPTPTPTPTPTPDKSHNSGVNISTL
  VLSVIGSVVIVNFILSTTI
• Function: May be involved in mediating calcium-activated chloride conductance.
• Tissue Specificity: Primarily expressed in the digestive tract, mainly in colon. Detected in smaller amounts in brain, urogenital organs, testis, and salivary and mammary glands. Highly expressed in the epithelial layer and submucosal gland of the inferior turbinate mucosa. Lower levels in the epithelial layer of nasal polyp.
• KEGG Pathway:
  Renin secretion (hsa04924)
  Pancreatic secretion (hsa04972)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatic encephalopathy	DISEAKAN	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[5]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[5]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[2]
Cystic fibrosis	DIS2OK1Q	Limited	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Calcium-activated chloride channel regulator 4 (CLCA4).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Calcium-activated chloride channel regulator 4 (CLCA4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Calcium-activated chloride channel regulator 4 (CLCA4).	[9]

References

• [1] Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study.Ann Intern Med. 2010 Sep 7;153(5):281-8. doi: 10.7326/0003-4819-153-5-201009070-00002.
• [2] Calcium-Activated Chloride Channel A4 (CLCA4) Plays Inhibitory Roles in Invasion and Migration Through Suppressing Epithelial-Mesenchymal Transition via PI3K/AKT Signaling in Colorectal Cancer.Med Sci Monit. 2019 Jun 5;25:4176-4185. doi: 10.12659/MSM.914195.
• [3] Correction: CLCA4 inhibits bladder cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT pathway.Oncotarget. 2019 Jan 29;10(9):1010. doi: 10.18632/oncotarget.26656. eCollection 2019 Jan 29.
• [4] Chloride Channel Accessory 4 (CLCA4) Gene Polymorphisms and Non-Obstructive Azoospermia: A Case-Control Study.Med Sci Monit. 2019 Mar 19;25:2043-2048. doi: 10.12659/MSM.915393.
• [5] Loss of CLCA4 promotes epithelial-to-mesenchymal transition in breast cancer cells.PLoS One. 2013 Dec 26;8(12):e83943. doi: 10.1371/journal.pone.0083943. eCollection 2013.
• [6] Naturally Occurring Deletion Mutants of the Pig-Specific, Intestinal Crypt Epithelial Cell Protein CLCA4b without Apparent Phenotype.PLoS One. 2015 Oct 16;10(10):e0140050. doi: 10.1371/journal.pone.0140050. eCollection 2015.
• [7] CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling.Aging (Albany NY). 2018 Oct 11;10(10):2570-2584. doi: 10.18632/aging.101571.
• [8] 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.
• [9] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [10] 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.