Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXEFL76)

• DOT Name: Leucine-rich repeat-containing protein 26 (LRRC26)
• Synonyms: BK channel auxiliary gamma subunit LRRC26; Cytokeratin-associated protein in cancer
• Gene Name: LRRC26
• Related Disease:
  Cystic fibrosis
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
• UniProt ID: LRC26_HUMAN
• PDB ID: 7YO3
• Pfam ID: PF13855
• Sequence:
  MRGPSWSRPRPLLLLLLLLSPWPVWAQVSATASPSGSLGAPDCPEVCTCVPGGLASCSAL
  SLPAVPPGLSLRLRALLLDHNRVRALPPGAFAGAGALQRLDLRENGLHSVHVRAFWGLGA
  LQLLDLSANQLEALAPGTFAPLRALRNLSLAGNRLARLEPAALGALPLLRSLSLQDNELA
  ALAPGLLGRLPALDALHLRGNPWGCGCALRPLCAWLRRHPLPASEAETVLCVWPGRLTLS
  PLTAFSDAAFSHCAQPLALRDLAVVYTLGPASFLVSLASCLALGSGLTACRARRRRLRTA
  ALRPPRPPDPNPDPDPHGCASPADPGSPAAAAQA
• Function: Auxiliary protein of the large-conductance, voltage and calcium-activated potassium channel (BK alpha). Required for the conversion of BK alpha channels from a high-voltage to a low-voltage activated channel type in non-excitable cells. These are characterized by negative membrane voltages and constant low levels of calcium.
• Tissue Specificity: Isoform 1 is expressed highly in normal prostate and salivary gland, very weakly in colon, pancreas, and intestine, and not at all in other tissues. Isoform 1 is expressed highly in many cancer cell lines and in breast cancer, pancreatic cancer and colon cancer. Isoform 2 is expressed in cancer cell lines.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[1]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	moderate	Biomarker	[3]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[3]
Prostate cancer	DISF190Y	moderate	Biomarker	[3]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]

3 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 Leucine-rich repeat-containing protein 26 (LRRC26).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Leucine-rich repeat-containing protein 26 (LRRC26).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Leucine-rich repeat-containing protein 26 (LRRC26).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Leucine-rich repeat-containing protein 26 (LRRC26).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Leucine-rich repeat-containing protein 26 (LRRC26).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Leucine-rich repeat-containing protein 26 (LRRC26).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Leucine-rich repeat-containing protein 26 (LRRC26).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Leucine-rich repeat-containing protein 26 (LRRC26).	[9]

References

• [1] Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis.Am J Respir Crit Care Med. 2020 Feb 1;201(3):313-324. doi: 10.1164/rccm.201905-0990OC.
• [2] Frequent downregulation of LRRC26 by epigenetic alterations is involved in the malignant progression of triple-negative breast cancer.Int J Oncol. 2018 May;52(5):1539-1558. doi: 10.3892/ijo.2018.4301. Epub 2018 Mar 5.
• [3] CAPC negatively regulates NF-B activation and suppresses tumor growth and metastasis.Oncogene. 2012 Mar 29;31(13):1673-82. doi: 10.1038/onc.2011.355. Epub 2011 Aug 8.
• [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] 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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [8] 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.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] 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.