Protumorigenic role of MDM4 in human hepatocarcinogenesis.
Final Report Abstract
MDM4 represents a well-known inhibitor of the most famous tumor suppressor gene p53, which is also known as the guardian of the genome. MDM4 blocks transcriptional activation mediated by p53 and has been previously described to be upregulated in human HCC. We have previously described genomic and post-transcriptional mechanisms involved in this protumorigenic dysrégulation of MDM4 in HCC, but our data supported a potential role of additional mechanisms affecting MDM4 mRNA abundance in HCC cells. In this project we provided evidence that the survival of some human HCC cells carrying a wildtype p53 gene depends on a basal level of MDM4 expression, which may represent an important vulnerability of these cells in terms of drug targeting. However, currently there is no biomarker allowing for a robust identification of HCC patients that may benefit from direct targeting MDM4. Using numerous meticulous experiments (including modulation of gene expression, promoter reporter assays, chromatin immunoprécipitation) we showed that a cluster of transcription factors, including SRF and its cofactors ELK1 and ELK4 activate the transcription of the MDM4 gene in HCC both in vitro and in vivo. Furthermore, we demonstrated that XI-011 represents a promising drug candidate for efficient targeting of MDM4 in cell culture, which warrants further evaluation in preclinical in vivo models. However, transposon-mediated MDM4 overexpression alone induced pre-neoplastic hepatocellular lesions in a mosaic mouse models, but was insufficient to induce malignant transformation into HCC without co-acting factors. Taken together, targeting MDM4 represents a promising approach in selected HCC patients, but further analyses are required to define the molecular constellation(s) leading to MDM4-dependent viability of (p53-wildtype?) HCC cells.
Publications
- RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer. Cancer Cell. 2017;31:94-109
Schneider AT, Gautheron J, Feoktistova M, Roderburg C, Loosen SH, Roy S, Benz F, Schemmer P, Büchler MW, Nachbur U, Neumann UP, Tolba R, Luedde M, Zucman-Rossi J, Panayotova-Dimitrova D, Leverkus M, Preisinger C, Tacke F, Trautwein C, Longerich T, Vucur M, Luedde T
(See online at https://doi.org/10.1016/j.ccell.2016.11.009) - Non-invasive diagnosis of hepatocellular carcinoma revisited. Gut. 2018; 67:991-993
Mueller C, Waldburger N, Stampfl U, Kauczor HU, Schirmacher P, Sommer CM, Longerich T
(See online at https://doi.org/10.1136/gutjnl-2017-314981) - RSPO2 gene rearrangement – a powerful driver of β-catenin activation in liver tumours. Gut. 2019
Longerich T, Endris V, Neumann O, Rempel E, Kirchner M, Abadi Z, Uhrig S, Kriegsmann M, Weiss KH, Breuhahn K, Mehrabi A, Weber TF, Wilkens L, Straub BK, Rosenwald A, Schulze F, Brors B, Fröhling S, Pellegrino V, Budczies J, Schirmacher P, Stenzinger A
(See online at https://doi.org/10.1136/gutjnl-2018-317632) - RSPO2 gene rearrangement – a powerful driver of βcatenin activation in liver tumours. Gut. 2019
Longerich T, Endris V, Neumann O, Rempel E, Kirchner M, Abadi Z, Uhrig S, Kriegsmann M, Weiss K-H, Breuhahn K, Mehrabi A, Weber TF, Wilkens L, Straub BK, Rosenwald A, Schulze F, Brors b, Fröhling S, Pellegrino R, Budczies J, Schirmacher P & Stenzinger A
(See online at https://doi.org/10.1136/gutjnl-2018-317632)
