MTDH

Function

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. MTDH has been shown to interact with spliceosome proteins in the cell nucleus and regulate the process of alternative splicing.

MTDH induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis. Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).

Clinical significance

MTDH acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma. 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.

MTDH has been shown to be overexpressed in prostate cancer, where there is a shift towards a more cytoplasmic localisation, signalling a poor prognosis. 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.

MTDH controls many hallmarks of oncogenes and cancer. MTDH/AEG-1 induces hepato steatosis in mouse liver. MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer. Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal cell physiology. Biomaterial titanium substrata with microgrooves can alter MTDH expression in human primary cells.

Interactions

MTDH has been shown to interact with:

• Nucleolin,

• NF-kB-p65 subunit,

References

References

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8. (January 2012). "Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9)". The Journal of Biological Chemistry.
9. (March 2009). "Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression". The Journal of Clinical Investigation.
10. (January 2009). "MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer". Cancer Cell.
11. (2021-11-29). "Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis". Nature Cancer.
12. (2021-11-29). "Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer". Nature Cancer.
13. "New cancer therapy from Yibin Kang's lab holds potential to switch off major cancer types without side effects".
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17. (November 2012). "Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model". Hepatology.
18. (2012). "Establishment and characterization of MTDH knockdown by artificial MicroRNA interference - functions as a potential tumor suppressor in breast cancer". Asian Pacific Journal of Cancer Prevention.
19. (November 2011). "Global profiling of dynamic protein palmitoylation". Nature Methods.
20. (April 2012). "The significance of differential expression of genes and proteins in human primary cells caused by microgrooved biomaterial substrata". Biomaterials.
21. (June 2021). "Identification of Nucleolin as a Novel AEG-1-Interacting Protein in Breast Cancer via Interactome Profiling". Cancers.
22. (March 2020). "A novel metadherinΔ7 splice variant enhances triple negative breast cancer aggressiveness by modulating mitochondrial function via NFĸB-SIRT3 axis". Oncogene.