Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOOCG4R)

• DOT Name: Serine/threonine-protein kinase LATS1 (LATS1)
• Synonyms: EC 2.7.11.1; Large tumor suppressor homolog 1; WARTS protein kinase; h-warts
• Gene Name: LATS1
• Related Disease:
  Anaplastic astrocytoma
  Bone osteosarcoma
  Breast cancer
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Malignant peripheral nerve sheath tumor
  Neoplasm
  Oligoastrocytoma
  Osteosarcoma
  Prostate neoplasm
  Renal cell carcinoma
  Schwannoma
  Stomach cancer
  Triple negative breast cancer
  Ulcerative colitis
  Astrocytoma
  Carcinoma
  Metastatic malignant neoplasm
  Squamous cell carcinoma
  Breast carcinoma
  Epithelial neoplasm
  Gastric cancer
  Glandular cell neoplasm
  Liver cancer
  Malignant soft tissue neoplasm
  Non-small-cell lung cancer
  Sarcoma
• UniProt ID: LATS1_HUMAN
• PDB ID: 4ZRK; 5B5W; 5BRK; 7LWH
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433 ; PF00627
• Sequence:
  MKRSEKPEGYRQMRPKTFPASNYTVSSRQMLQEIRESLRNLSKPSDAAKAEHNMSKMSTE
  DPRQVRNPPKFGTHHKALQEIRNSLLPFANETNSSRSTSEVNPQMLQDLQAAGFDEDMVI
  QALQKTNNRSIEAAIEFISKMSYQDPRREQMAAAAARPINASMKPGNVQQSVNRKQSWKG
  SKESLVPQRHGPPLGESVAYHSESPNSQTDVGRPLSGSGISAFVQAHPSNGQRVNPPPPP
  QVRSVTPPPPPRGQTPPPRGTTPPPPSWEPNSQTKRYSGNMEYVISRISPVPPGAWQEGY
  PPPPLNTSPMNPPNQGQRGISSVPVGRQPIIMQSSSKFNFPSGRPGMQNGTGQTDFMIHQ
  NVVPAGTVNRQPPPPYPLTAANGQSPSALQTGGSAAPSSYTNGSIPQSMMVPNRNSHNME
  LYNISVPGLQTNWPQSSSAPAQSSPSSGHEIPTWQPNIPVRSNSFNNPLGNRASHSANSQ
  PSATTVTAITPAPIQQPVKSMRVLKPELQTALAPTHPSWIPQPIQTVQPSPFPEGTASNV
  TVMPPVAEAPNYQGPPPPYPKHLLHQNPSVPPYESISKPSKEDQPSLPKEDESEKSYENV
  DSGDKEKKQITTSPITVRKNKKDEERRESRIQSYSPQAFKFFMEQHVENVLKSHQQRLHR
  KKQLENEMMRVGLSQDAQDQMRKMLCQKESNYIRLKRAKMDKSMFVKIKTLGIGAFGEVC
  LARKVDTKALYATKTLRKKDVLLRNQVAHVKAERDILAEADNEWVVRLYYSFQDKDNLYF
  VMDYIPGGDMMSLLIRMGIFPESLARFYIAELTCAVESVHKMGFIHRDIKPDNILIDRDG
  HIKLTDFGLCTGFRWTHDSKYYQSGDHPRQDSMDFSNEWGDPSSCRCGDRLKPLERRAAR
  QHQRCLAHSLVGTPNYIAPEVLLRTGYTQLCDWWSVGVILFEMLVGQPPFLAQTPLETQM
  KVINWQTSLHIPPQAKLSPEASDLIIKLCRGPEDRLGKNGADEIKAHPFFKTIDFSSDLR
  QQSASYIPKITHPTDTSNFDPVDPDKLWSDDNEEENVNDTLNGWYKNGKHPEHAFYEFTF
  RRFFDDNGYPYNYPKPIEYEYINSQGSEQQSDEDDQNTGSEIKNRDLVYV
• Function: Negative regulator of YAP1 in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Acts as a tumor suppressor which plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G1 tetraploidy checkpoint. Negatively regulates G2/M transition by down-regulating CDK1 kinase activity. Involved in the control of p53 expression. Affects cytokinesis by regulating actin polymerization through negative modulation of LIMK1. May also play a role in endocrine function. Plays a role in mammary gland epithelial cell differentiation, both through the Hippo signaling pathway and the intracellular estrogen receptor signaling pathway by promoting the degradation of ESR1.
• Tissue Specificity: Expressed in all adult tissues examined except for lung and kidney.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway: Signaling by Hippo (R-HSA-2028269)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anaplastic astrocytoma	DISSBE0K	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Posttranslational Modification	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Oligoastrocytoma	DISQGE8F	Strong	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[9]
Schwannoma	DISTTVLA	Strong	Biomarker	[15]
Stomach cancer	DISKIJSX	Strong	Biomarker	[16]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[17]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[11]
Astrocytoma	DISL3V18	moderate	Biomarker	[1]
Carcinoma	DISH9F1N	moderate	Posttranslational Modification	[18]
Metastatic malignant neoplasm	DIS86UK6	moderate	Posttranslational Modification	[19]
Squamous cell carcinoma	DISQVIFL	moderate	Posttranslational Modification	[18]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[3]
Epithelial neoplasm	DIS0T594	Limited	Biomarker	[20]
Gastric cancer	DISXGOUK	Limited	Biomarker	[21]
Glandular cell neoplasm	DISTDLVN	Limited	Biomarker	[20]
Liver cancer	DISDE4BI	Limited	Altered Expression	[22]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Genetic Variation	[23]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[24]
Sarcoma	DISZDG3U	Limited	Genetic Variation	[23]

12 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 Serine/threonine-protein kinase LATS1 (LATS1).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[29]
Marinol	DM70IK5	Approved	Marinol increases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[31]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[33]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[36]
LICOAGROCHACONE A	DMWY0TN	Investigative	LICOAGROCHACONE A decreases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[38]
gingerol	DMNXYSM	Investigative	gingerol increases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[39]
Ginsenoside RG3	DMFN58T	Investigative	Ginsenoside RG3 increases the expression of Serine/threonine-protein kinase LATS1 (LATS1).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Serine/threonine-protein kinase LATS1 (LATS1).	[1]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the phosphorylation of Serine/threonine-protein kinase LATS1 (LATS1).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Serine/threonine-protein kinase LATS1 (LATS1).	[34]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase LATS1 (LATS1).	[37]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/threonine-protein kinase LATS1 (LATS1).	[37]

References

• [1] Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res. 2006 Dec;56(4):450-8. doi: 10.1016/j.neures.2006.09.006. Epub 2006 Oct 17.
• [2] ELK1-induced upregulation of long non-coding RNA MIR100HG predicts poor prognosis and promotes the progression of osteosarcoma by epigenetically silencing LATS1 and LATS2.Biomed Pharmacother. 2019 Jan;109:788-797. doi: 10.1016/j.biopha.2018.10.029. Epub 2018 Nov 5.
• [3] A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1.Protein Cell. 2019 Aug;10(8):595-605. doi: 10.1007/s13238-019-0607-2. Epub 2019 Feb 1.
• [4] Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers.Clin Cancer Res. 2005 Feb 15;11(4):1380-5. doi: 10.1158/1078-0432.CCR-04-1773.
• [5] LATS1 suppresses proliferation and invasion of cervical cancer.Mol Med Rep. 2017 Apr;15(4):1654-1660. doi: 10.3892/mmr.2017.6180. Epub 2017 Feb 8.
• [6] The Immunoexpression of YAP1 and LATS1 Proteins in Clear Cell Renal Cell Carcinoma: Impact on Patients' Survival.Biomed Res Int. 2018 Apr 3;2018:2653623. doi: 10.1155/2018/2653623. eCollection 2018.
• [7] REG Controls Hippo Signaling and Reciprocal NF-B-YAP Regulation to Promote Colon Cancer.Clin Cancer Res. 2018 Apr 15;24(8):2015-2025. doi: 10.1158/1078-0432.CCR-17-2986. Epub 2018 Feb 6.
• [8] Abnormal increase of miR-4262 promotes cell proliferation and migration by targeting large tumor suppressor 1 in gliomas.Pathol Res Pract. 2020 Feb;216(2):152778. doi: 10.1016/j.prp.2019.152778. Epub 2019 Dec 2.
• [9] Methylationassociated inactivation of LATS1 and its effect on demethylation or overexpression on YAP and cell biological function in human renal cell carcinoma.Int J Oncol. 2014 Dec;45(6):2511-21. doi: 10.3892/ijo.2014.2687. Epub 2014 Sep 30.
• [10] miR-29c-3p regulates DNMT3B and LATS1 methylation to inhibit tumor progression in hepatocellular carcinoma.Cell Death Dis. 2019 Jan 18;10(2):48. doi: 10.1038/s41419-018-1281-7.
• [11] Immunohistochemical Profile of Tumor Suppressor Proteins RASSF1A and LATS1/2 in Relation to p73 and YAP Expression, of Human Inflammatory Bowel Disease and Normal Intestine.Pathol Oncol Res. 2020 Jan;26(1):567-574. doi: 10.1007/s12253-018-00575-z. Epub 2019 Jan 2.
• [12] TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer.Mol Carcinog. 2018 Feb;57(2):159-166. doi: 10.1002/mc.22740. Epub 2017 Dec 5.
• [13] Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis.Cancer Cell. 2018 Feb 12;33(2):292-308.e7. doi: 10.1016/j.ccell.2018.01.005.
• [14] Loss of Par3 promotes prostatic tumorigenesis by enhancing cell growth and changing cell division modes.Oncogene. 2019 Mar;38(12):2192-2205. doi: 10.1038/s41388-018-0580-x. Epub 2018 Nov 22.
• [15] Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas.J Neuropathol Exp Neurol. 2015 Oct;74(10):952-9. doi: 10.1097/NEN.0000000000000238.
• [16] Over-expression of oncigenic pesudogene DUXAP10 promotes cell proliferation and invasion by regulating LATS1 and -catenin in gastric cancer.J Exp Clin Cancer Res. 2018 Jan 27;37(1):13. doi: 10.1186/s13046-018-0684-8.
• [17] Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy.Cancer Biol Ther. 2017 May 4;18(5):339-346. doi: 10.1080/15384047.2017.1312230. Epub 2017 Apr 7.
• [18] Hypermethylation of promoter region of LATS1--a CDK interacting protein in oral squamous cell carcinomas--a pilot study in India.Asian Pac J Cancer Prev. 2015;16(4):1599-603. doi: 10.7314/apjcp.2015.16.4.1599.
• [19] Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome.Oncol Rep. 2017 Jul;38(1):427-439. doi: 10.3892/or.2017.5642. Epub 2017 May 15.
• [20] A transgenic Drosophila model for arsenic methylation suggests a metabolic rationale for differential dose-dependent toxicity endpoints.Toxicol Sci. 2011 Jun;121(2):303-11. doi: 10.1093/toxsci/kfr074. Epub 2011 Mar 29.
• [21] High Yes-associated protein 1 with concomitant negative LATS1/2 expression is associated with poor prognosis of advanced gastric cancer.Pathology. 2019 Apr;51(3):261-267. doi: 10.1016/j.pathol.2019.01.001. Epub 2019 Feb 25.
• [22] Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling.Oncotarget. 2017 May 2;8(18):29785-29794. doi: 10.18632/oncotarget.14523.
• [23] The Hippo signal transduction pathway in soft tissue sarcomas.Biochim Biophys Acta. 2015 Aug;1856(1):121-9. doi: 10.1016/j.bbcan.2015.05.006. Epub 2015 Jun 4.
• [24] Molecular Alterations and Expression Dynamics of LATS1 and LATS2 Genes in Non-Small-Cell Lung Carcinoma.Pathol Oncol Res. 2018 Apr;24(2):207-214. doi: 10.1007/s12253-017-0225-3. Epub 2017 Apr 22.
• [25] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [26] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [27] 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.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [30] Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res. 2006 Dec;56(4):450-8. doi: 10.1016/j.neures.2006.09.006. Epub 2006 Oct 17.
• [31] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [32] The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells. Chem Biol Interact. 2019 Apr 1;302:28-35. doi: 10.1016/j.cbi.2019.01.033. Epub 2019 Jan 28.
• [33] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [34] 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.
• [35] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [36] 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.
• [37] 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.
• [38] Licochalcone A inhibits cell growth through the downregulation of the Hippo pathway via PES1 in cholangiocarcinoma cells. Environ Toxicol. 2022 Mar;37(3):564-573. doi: 10.1002/tox.23422. Epub 2021 Nov 30.
• [39] 6-Gingerol suppresses tumor cell metastasis by increasing YAP(ser127) phosphorylation in renal cell carcinoma. J Biochem Mol Toxicol. 2021 Jan;35(1):e22609. doi: 10.1002/jbt.22609. Epub 2020 Sep 14.
• [40] Ginsenoside Rg3 attenuates the osimertinib resistance by reducing the stemness of non-small cell lung cancer cells. Environ Toxicol. 2020 Jun;35(6):643-651. doi: 10.1002/tox.22899. Epub 2020 Jan 9.