Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3DLX0)

• DOT Name: Metastasis-associated in colon cancer protein 1 (MACC1)
• Synonyms: SH3 domain-containing protein 7a5
• Gene Name: MACC1
• Related Disease:
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Adenoma
  Adult glioblastoma
  Astrocytoma
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Cervical cancer
  Cholangiocarcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Congenital contractural arachnodactyly
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Malignant glioma
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Squamous cell carcinoma
  Stomach cancer
  Carcinoma
  Nasopharyngeal carcinoma
  Non-small-cell lung cancer
  Adenocarcinoma
  Cervical carcinoma
  Colon adenocarcinoma
  Colorectal adenocarcinoma
  Colorectal adenoma
  Gallbladder carcinoma
  Melanoma
  Rectal carcinoma
• UniProt ID: MACC1_HUMAN
• Sequence:
  MLITERKHFRSGRIAQSMSEANLIDMEAGKLSKSCNITECQDPDLLHNWPDAFTLRGNNA
  SKVANPFWNQLSASNPFLDDITQLRNNRKRNNISILKEDPFLFCREIENGNSFDSSGDEL
  DVHQLLRQTSSRNSGRSKSVSELLDILDDTAHAHQSIHNSDQILLHDLEWLKNDREAYKM
  AWLSQRQLARSCLDLNTISQSPGWAQTQLAEVTIACKVNHQGGSVQLPESDITVHVPQGH
  VAVGEFQEVSLRAFLDPPHMLNHDLSCTVSPLLEIMLGNLNTMEALLLEMKIGAEVRKDP
  FSQVMTEMVCLHSLGKEGPFKVLSNCYIYKDTIQVKLIDLSQVMYLVVAAQAKALPSPAA
  TIWDYIHKTTSIGIYGPKYIHPSFTVVLTVCGHNYMPGQLTISDIKKGGKNISPVVFQLW
  GKQSFLLDKPQDLSISIFSCDPDFEVKTEGERKEIKQKQLEAGEVVHQQFLFSLVEHREM
  HLFDFCVQVEPPNGEPVAQFSITTPDPTPNLKRLSNLPGYLQKKEEIKSAPLSPKILVKY
  PTFQDKTLNFSNYGVTLKAVLRQSKIDYFLEYFKGDTIALLGEGKVKAIGQSKVKEWYVG
  VLRGKIGLVHCKNVKVISKEQVMFMSDSVFTTRNLLEQIVLPLKKLTYIYSVVLTLVSEK
  VYDWKVLADVLGYSHLSLEDFDQIQADKESEKVSYVIKKLKEDCHTERNTRKFLYELIVA
  LLKMDCQELVARLIQEAAVLTSAVKLGKGWRELAEKLVRLTKQQMEAYEIPHRGNTGDVA
  VEMMWKPAYDFLYTWSAHYGNNYRDVLQDLQSALDRMKNPVTKHWRELTGVLILVNSLEV
  LRVTAFSTSEEV
• Function: Acts as a transcription activator for MET and as a key regulator of HGF-MET signaling. Promotes cell motility, proliferation and hepatocyte growth factor (HGF)-dependent scattering in vitro and tumor growth and metastasis in vivo.
• Tissue Specificity: Preferentially expressed in metastasizing tumors.

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Genetic Variation	[2]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Astrocytoma	DISL3V18	Strong	Altered Expression	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[7]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[8]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[9]
Cervical cancer	DISFSHPF	Strong	Biomarker	[10]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[11]
Colon cancer	DISVC52G	Strong	Altered Expression	[12]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[13]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[14]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Altered Expression	[11]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[15]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[16]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[17]
Gastric cancer	DISXGOUK	Strong	Biomarker	[18]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[19]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[20]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[21]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[22]
Lung cancer	DISCM4YA	Strong	Altered Expression	[23]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[23]
Malignant glioma	DISFXKOV	Strong	Biomarker	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[24]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[24]
Pancreatic cancer	DISJC981	Strong	Biomarker	[25]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[17]
Stomach cancer	DISKIJSX	Strong	Biomarker	[18]
Carcinoma	DISH9F1N	moderate	Altered Expression	[26]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[27]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[28]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[14]
Cervical carcinoma	DIST4S00	Limited	Biomarker	[10]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[29]
Colorectal adenocarcinoma	DISPQOUB	Limited	Altered Expression	[30]
Colorectal adenoma	DISTSVHM	Limited	Altered Expression	[14]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[31]
Melanoma	DIS1RRCY	Limited	Altered Expression	[32]
Rectal carcinoma	DIS8FRR7	Limited	Altered Expression	[33]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Metastasis-associated in colon cancer protein 1 (MACC1) increases the Neutropenia ADR of Etoposide.	[44]

4 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 Metastasis-associated in colon cancer protein 1 (MACC1).	[34]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Metastasis-associated in colon cancer protein 1 (MACC1).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metastasis-associated in colon cancer protein 1 (MACC1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Metastasis-associated in colon cancer protein 1 (MACC1).	[39]

9 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 Metastasis-associated in colon cancer protein 1 (MACC1).	[35]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[36]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[37]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[38]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[38]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Metastasis-associated in colon cancer protein 1 (MACC1).	[43]

References

• [1] MACC1 overexpression in carcinomaassociated fibroblasts induces the invasion of lung adenocarcinoma cells via paracrine signaling.Int J Oncol. 2019 Apr;54(4):1367-1375. doi: 10.3892/ijo.2019.4702. Epub 2019 Jan 30.
• [2] Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence.Surg Oncol. 2018 Jun;27(2):280-288. doi: 10.1016/j.suronc.2018.05.012. Epub 2018 May 8.
• [3] Increased MACC1 levels in tissues and blood identify colon adenoma patients at high risk.J Transl Med. 2016 Jul 20;14(1):215. doi: 10.1186/s12967-016-0971-0.
• [4] Circulating MACC1 Transcripts in Glioblastoma Patients Predict Prognosis and Treatment Response.Cancers (Basel). 2019 Jun 13;11(6):825. doi: 10.3390/cancers11060825.
• [5] Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.Neuro Oncol. 2013 Dec;15(12):1696-709. doi: 10.1093/neuonc/not136. Epub 2013 Nov 11.
• [6] MicroRNA-432 is downregulated in osteosarcoma and inhibits cell proliferation and invasion by directly targeting metastasis-associated in colon cancer-1.Exp Ther Med. 2019 Jan;17(1):919-926. doi: 10.3892/etm.2018.7029. Epub 2018 Nov 29.
• [7] Genetic Variation in Metastasis-Associated in Colon Cancer-1 and the Risk of Breast Cancer Among the Chinese Han Population: A STROBE-Compliant Observational Study.Medicine (Baltimore). 2016 Feb;95(6):e2801. doi: 10.1097/MD.0000000000002801.
• [8] LncRNA MACC1-AS1 sponges multiple miRNAs and RNA-binding protein PTBP1.Oncogenesis. 2019 Dec 10;8(12):73. doi: 10.1038/s41389-019-0182-7.
• [9] Downregulation of MACC1 inhibits the viability, invasion and migration and induces apoptosis in esophageal carcinoma cells through the phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B signaling pathway.Oncol Lett. 2017 Oct;14(4):4897-4905. doi: 10.3892/ol.2017.6790. Epub 2017 Aug 23.
• [10] Overexpression of circular RNA hsa_circ_0001038 promotes cervical cancer cell progression by acting as a ceRNA for miR-337-3p to regulate cyclin-M3 and metastasis-associated in colon cancer 1 expression.Gene. 2020 Apr 5;733:144273. doi: 10.1016/j.gene.2019.144273. Epub 2019 Dec 3.
• [11] MACC1 promotes angiogenesis in cholangiocarcinoma by upregulating VEGFA.Onco Targets Ther. 2019 Mar 8;12:1893-1903. doi: 10.2147/OTT.S197319. eCollection 2019.
• [12] DBC1 regulates Wnt/-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer.Cell Death Dis. 2018 Aug 6;9(8):831. doi: 10.1038/s41419-018-0899-9.
• [13] Prognostic and Risk Stratification Value of Lesion MACC1 Expression in Colorectal Cancer Patients.Front Oncol. 2019 Feb 5;9:28. doi: 10.3389/fonc.2019.00028. eCollection 2019.
• [14] MACC1 is related to colorectal cancer initiation and early-stage invasive growth.Am J Clin Pathol. 2013 Nov;140(5):701-7. doi: 10.1309/AJCPRH1H5RWWSXRB.
• [15] Correlation of MACC1/c-Myc Expression in Endometrial Carcinoma with Clinical/Pathological Features or Prognosis.Med Sci Monit. 2018 Jul 9;24:4738-4744. doi: 10.12659/MSM.908812.
• [16] Down-regulation of miR-338-3p and Up-regulation of MACC1 Indicated Poor Prognosis of Epithelial Ovarian Cancer Patients.J Cancer. 2019 Feb 23;10(6):1385-1392. doi: 10.7150/jca.29502. eCollection 2019.
• [17] MACC1 induces autophagy to regulate proliferation, apoptosis, migration and invasion of squamous cell carcinoma.Oncol Rep. 2017 Oct;38(4):2369-2377. doi: 10.3892/or.2017.5889. Epub 2017 Aug 8.
• [18] Clinicopathological and prognostic significance of metastasis-associated in colon cancer-1 in gastric cancer: A meta-analysis.Int J Biol Markers. 2019 Mar;34(1):27-32. doi: 10.1177/1724600818813634. Epub 2019 Mar 10.
• [19] Silence of MACC1 expression by RNA interference inhibits proliferation, invasion and metastasis, and promotes apoptosis in U251 human malignant glioma cells.Mol Med Rep. 2015 Sep;12(3):3423-3431. doi: 10.3892/mmr.2015.3886. Epub 2015 Jun 3.
• [20] MiR-302 a/b/c suppresses tumor angiogenesis in hepatocellular carcinoma by targeting MACC1.Eur Rev Med Pharmacol Sci. 2019 Sep;23(18):7863-7873. doi: 10.26355/eurrev_201909_18996.
• [21] Metastasis-associated in colon cancer 1 is an independent prognostic biomarker for survival in Klatskin tumor patients.Hepatology. 2015 Sep;62(3):841-50. doi: 10.1002/hep.27885. Epub 2015 Jun 26.
• [22] High intratumoral metastasis-associated in colon cancer-1 expression predicts poor outcomes of cryoablation therapy for advanced hepatocellular carcinoma.J Transl Med. 2013 Feb 15;11:41. doi: 10.1186/1479-5876-11-41.
• [23] Cisplatin resistance in lung cancer is mediated by MACC1 expression through PI3K/AKT signaling pathway activation.Acta Biochim Biophys Sin (Shanghai). 2018 Aug 1;50(8):748-756. doi: 10.1093/abbs/gmy074.
• [24] Effects of metastasis-associated in colon cancer 1 inhibition by small hairpin RNA on ovarian carcinoma OVCAR-3 cells.J Exp Clin Cancer Res. 2011 Sep 16;30(1):83. doi: 10.1186/1756-9966-30-83.
• [25] Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer.Cancer Lett. 2018 Sep 28;432:237-250. doi: 10.1016/j.canlet.2018.04.035. Epub 2018 Apr 28.
• [26] Prognostic value and clinical pathology of MACC-1 and c-MET expression in gastric carcinoma.Pathol Oncol Res. 2013 Oct;19(4):821-32. doi: 10.1007/s12253-013-9650-0. Epub 2013 Jul 1.
• [27] MACC1 down-regulation inhibits proliferation and tumourigenicity of nasopharyngeal carcinoma cells through Akt/-catenin signaling pathway.PLoS One. 2013;8(4):e60821. doi: 10.1371/journal.pone.0060821. Epub 2013 Apr 3.
• [28] Circular RNA circ-FOXM1 facilitates cell progression as ceRNA to target PPDPF and MACC1 by sponging miR-1304-5p in non-small cell lung cancer.Biochem Biophys Res Commun. 2019 May 21;513(1):207-212. doi: 10.1016/j.bbrc.2019.03.213. Epub 2019 Apr 4.
• [29] Evaluation of the correlation of MACC1, CD44, Twist1, and KiSS-1 in the metastasis and prognosis for colon carcinoma.Diagn Pathol. 2018 Jul 18;13(1):45. doi: 10.1186/s13000-018-0722-z.
• [30] Heterogeneity analysis of Metastasis Associated in Colon Cancer 1 (MACC1) for survival prognosis of colorectal cancer patients: a retrospective cohort study.BMC Cancer. 2015 Mar 21;15:160. doi: 10.1186/s12885-015-1150-z.
• [31] Downregulated expression of metastasis associated in colon cancer 1 (MACC1) reduces gallbladder cancer cell proliferation and invasion.Tumour Biol. 2014 Apr;35(4):3771-8. doi: 10.1007/s13277-013-1499-z. Epub 2014 Jan 15.
• [32] MicroRNA-338-3p suppresses cell proliferation, migration and invasion in human malignant melanoma by targeting MACC1.Exp Ther Med. 2019 Aug;18(2):997-1004. doi: 10.3892/etm.2019.7644. Epub 2019 Jun 4.
• [33] Correlation of MACC1 and MET expression in rectal cancer after neoadjuvant chemoradiotherapy.Anticancer Res. 2012 Apr;32(4):1527-31.
• [34] 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.
• [35] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [36] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [37] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [38] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [39] 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.
• [40] 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.
• [41] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [42] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [43] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [44] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.