MTDH

MTDH (AEG-1) is involved in HIF-1alpha mediated angiogenesis. MTDH also interacts with SND1 and involved in RNA-induced silencing complex (RISC) and plays very important role in RISC and miRNA functions.{{cite journal | vauthors = Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia S, Pannell L, Fisher PB, Sarkar D | display-authors = 6 | title = Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma | journal = Hepatology | volume = 53 | issue = 5 | pages = 1538–48 | date = May 2011 | pmid = 21520169 | pmc = 3081619 | doi = 10.1002/hep.24216 }}{{cite journal | vauthors = Yoo BK, Emdad L, Lee SG, Su ZZ, Santhekadur P, Chen D, Gredler R, Fisher PB, Sarkar D | display-authors = 6 | title = Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology | journal = Pharmacology & Therapeutics | volume = 130 | issue = 1 | pages = 1–8 | date = April 2011 | pmid = 21256156 | pmc = 3043119 | doi = 10.1016/j.pharmthera.2011.01.008 }} MTDH has been shown to interact with spliceosome proteins in the cell nucleus and regulate the process of alternative splicing.{{cite journal| vauthors = Luxton HJ, Simpson BS, Mills IG, Brindle NR, Ahmed Z, Stavrinides V, Heavey S, Stamm S, Whitaker HC |date = September 2019 |title=The Oncogene Metadherin Interacts with the Known Splicing Proteins YTHDC1, Sam68 and T-STAR and Plays a Novel Role in Alternative mRNA Splicing|journal=Cancers |volume=11|issue=9|pages=1233|doi=10.3390/cancers11091233|pmid = 31450747 |pmc = 6770463 |doi-access=free}}

MTDH induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis.{{cite journal | vauthors = Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T, Shah K, Saxena U, Hansen U, Fisher PB, Sarkar D | display-authors = 6 | title = Identification of genes conferring resistance to 5-fluorouracil | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 31 | pages = 12938–43 | date = August 2009 | pmid = 19622726 | pmc = 2722317 | doi = 10.1073/pnas.0901451106 | bibcode = 2009PNAS..10612938Y | doi-access = free }} Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).{{cite journal | vauthors = Santhekadur PK, Gredler R, Chen D, Siddiq A, Shen XN, Das SK, Emdad L, Fisher PB, Sarkar D | display-authors = 6 | title = Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9) | journal = The Journal of Biological Chemistry | volume = 287 | issue = 5 | pages = 3425–32 | date = January 2012 | pmid = 22167195 | pmc = 3270996 | doi = 10.1074/jbc.M111.298976 | doi-access = free }}

MTDH acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma.{{cite journal | vauthors = Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, Mills AS, Waxman S, Fisher RA, Llovet JM, Fisher PB, Sarkar D | display-authors = 6 | title = Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression | journal = The Journal of Clinical Investigation | volume = 119 | issue = 3 | pages = 465–77 | date = March 2009 | pmid = 19221438 | pmc = 2648696 | doi = 10.1172/JCI36460 }} It is highly expressed in these cancers and helps in their progression and development. It is induced by c-Myc oncogene and plays an important role in anchorage independent growth of cancer cells (metastasis).

Elevated expression of MTDH, which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting metastatic seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing chemotherapy and reducing metastasis.{{cite journal | vauthors = Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG, Kang Y | display-authors = 6 | title = MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer | journal = Cancer Cell | volume = 15 | issue = 1 | pages = 9–20 | date = January 2009 | pmid = 19111877 | pmc = 2676231 | doi = 10.1016/j.ccr.2008.11.013 | author-link10 = Yibin Kang }}{{Cite journal| vauthors = Shen M, Wei Y, Kim H, Wan L, Jiang YZ, Hang X, Raba M, Remiszewski S, Rowicki M, Wu CG, Wu S | display-authors = 6 |date=2021-11-29|title=Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis |journal=Nature Cancer| volume = 3 | issue = 1 |language=en|pages=43–59|doi=10.1038/s43018-021-00279-5| pmid = 35121987 | pmc = 8818087 |issn=2662-1347}}{{Cite journal| vauthors = Shen M, Smith HA, Wei Y, Jiang YZ, Zhao S, Wang N, Rowicki M, Tang Y, Hang X, Wu S, Wan L | display-authors = 6 |date=2021-11-29|title=Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer |journal=Nature Cancer| volume = 3 | issue = 1 | pages = 60–74 |language=en|doi=10.1038/s43018-021-00280-y| pmid = 35121988 | pmc = 8818088 |issn=2662-1347}}{{Cite web|title=New cancer therapy from Yibin Kang's lab holds potential to switch off major cancer types without side effects|url=https://www.princeton.edu/news/2021/11/29/new-cancer-therapy-yibin-kangs-lab-holds-potential-switch-major-cancer-types|access-date=2021-12-10|website=Princeton University|language=en}}

MTDH has been shown to be overexpressed in prostate cancer, where there is a shift towards a more cytoplasmic localisation, signalling a poor prognosis.{{cite journal |last1=Dhiman |first1=Gourav |last2=Srivastava |first2=Neha |last3=Goyal |first3=Mehendi |last4=Rakha |first4=Emad |last5=Lothion-Roy |first5=Jennifer |last6=Mongan |first6=Nigel P. |last7=Miftakhova |first7=Regina R. |last8=Khaiboullina |first8=Svetlana F. |last9=Rizvanov |first9=Albert A. |last10=Baranwal |first10=Manoj |title=Metadherin: A Therapeutic Target in Multiple Cancers |journal=Frontiers in Oncology |date=3 May 2019 |volume=9 |doi=10.3389/fonc.2019.00349|doi-access=free |pmid=31131259 |pmc=6509227 }}{{cite journal | vauthors = Thirkettle HJ, Girling J, Warren AY, Mills IG, Sahadevan K, Leung H, Hamdy F, Whitaker HC, Neal DE | display-authors = 6 | title = LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals | journal = Clinical Cancer Research | volume = 15 | issue = 9 | pages = 3003–13 | date = May 2009 | pmid = 19383828 | doi = 10.1158/1078-0432.CCR-08-2046 | doi-access = free }} In the nucleus of prostate cancer cells, MTDH has been shown to affect alternative splicing of genes such as CD44, which may also be associated with prostate cancer progression.

LSF/TFCP2 plays a multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer's disease.{{cite journal | vauthors = Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SC, Hansen U, Fisher PB, Sarkar D | year = 2012 | title = The transcription factor LSF: a novel oncogene for hepatocellular carcinoma | journal = Am J Cancer Res | volume = 2 | issue = 3 | pages = 269–285 | pmid = 22679558 | pmc = 3365805 | url = http://www.ajcr.us/files/ajcr0000110.pdf}}

MTDH controls many hallmarks of oncogenes and cancer. MTDH/AEG-1 induces hepato steatosis in mouse liver.{{cite journal | vauthors = Srivastava J, Siddiq A, Emdad L, Santhekadur PK, Chen D, Gredler R, Shen XN, Robertson CL, Dumur CI, Hylemon PB, Mukhopadhyay ND, Bhere D, Shah K, Ahmad R, Giashuddin S, Stafflinger J, Subler MA, Windle JJ, Fisher PB, Sarkar D | display-authors = 6 | title = Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model | journal = Hepatology | volume = 56 | issue = 5 | pages = 1782–91 | date = November 2012 | pmid = 22689379 | pmc = 3449036 | doi = 10.1002/hep.25868 }} MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer.{{cite journal | vauthors = Wang S, Shu JZ, Cai Y, Bao Z, Liang QM | title = Establishment and characterization of MTDH knockdown by artificial MicroRNA interference - functions as a potential tumor suppressor in breast cancer | journal = Asian Pacific Journal of Cancer Prevention | volume = 13 | issue = 6 | pages = 2813–8 | year = 2012 | pmid = 22938464 | doi = 10.7314/apjcp.2012.13.6.2813 | url = http://www.apocpcontrol.org/paper_file/issue_abs/Volume13_No6/2813-18%205.23%20Song%20Wang.pdf | doi-access = free }} Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal cell physiology.{{cite journal | vauthors = Martin BR, Wang C, Adibekian A, Tully SE, Cravatt BF | title = Global profiling of dynamic protein palmitoylation | journal = Nature Methods | volume = 9 | issue = 1 | pages = 84–9 | date = November 2011 | pmid = 22056678 | pmc = 3248616 | doi = 10.1038/nmeth.1769 }} Biomaterial titanium substrata with microgrooves can alter MTDH expression in human primary cells.{{cite journal | vauthors = Lee MH, Kang JH, Lee SW | title = The significance of differential expression of genes and proteins in human primary cells caused by microgrooved biomaterial substrata | journal = Biomaterials | volume = 33 | issue = 11 | pages = 3216–34 | date = April 2012 | pmid = 22285466 | doi = 10.1016/j.biomaterials.2012.01.034 }}

MTDH has been shown to interact with:

• Nucleolin,{{cite journal | vauthors = Lee SJ, Choi KM, Bang G, Park SG, Kim EB, Choi JW, Chung YH, Kim J, Lee SG, Kim E, Kim JY | display-authors = 6 | title = Identification of Nucleolin as a Novel AEG-1-Interacting Protein in Breast Cancer via Interactome Profiling | journal = Cancers | volume = 13 | issue = 11 | pages = 2842 | date = June 2021 | pmid = 34200450 | doi = 10.3390/cancers13112842 | pmc = 8201222 | s2cid = 235436955 | doi-access = free }}

• NF-kB-p65 subunit, {{cite journal | vauthors = Neeli PK, Gollavilli PN, Mallappa S, Hari SG, Kotamraju S | title = A novel metadherinΔ7 splice variant enhances triple negative breast cancer aggressiveness by modulating mitochondrial function via NFĸB-SIRT3 axis | journal = Oncogene | volume = 39 | issue = 10 | pages = 2088–2102 | date = March 2020 | pmid = 31806873 | doi = 10.1038/s41388-019-1126-6 | s2cid = 208648747 }}

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• {{cite journal | vauthors = Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB | title = Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 46 | pages = 17390–5 | date = November 2006 | pmid = 17088530 | pmc = 1859939 | doi = 10.1073/pnas.0608386103 | bibcode = 2006PNAS..10317390L | doi-access = free }}

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Category:Breast cancer