Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Abstract

Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.

MDMX in Cancer: A Partner of p53 and a p53-Independent Effector

“… 59 Metastatic Prostate Cancer Whether p53 is mutated or not, overexpression of MDMX in prostate cancer is implicated in apoptosis or senescence. 75 Lung Cancer Non-Small Cell Lung Cancer High expression of MDMX is associated with poorly differentiated tumor cells, advanced TNM staging, and the occurrence of lymph node metastasis. 76 Non-Small Cell Lung Cancer Overexpression of MDMX affects prognosis in NSCLC patients, which is associated with MDMX regulation of NSCLC cell proliferation and chemotherapy sensitivity.…”

Targeting the deubiquitinase USP2 for malignant tumor therapy (Review)

“…Previous studies have reported that MDM4 can promote endogenous apoptosis by regulating the expression of oncogene p53 and that USP2a can interact with MDM4 to inhibit its ubiquitin-mediated degradation ( 91 , 136 , 137 ). The expression of MDM4 and USP2a is significantly lower in GBM tissues than in normal brain tissues and is positively associated with the prognosis of GBM; that is, the higher the expression, the more improved the prognosis.…”

The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer

“…We identify edges that are most enriched in our GWAS+ cluster which could be pointing to essential links between the gene encoding for the node and containing a PrCa predisposing SNP at a particular EPIN. For example, we identify the link between MDM4 containing SNP rs35946963 (PrCa p-value 1e−24) and TP53 37 and between KDM2A containing SNP rs12790261 (PrCa p-value 1e−7) and BCL6 38 and ARNT continuing SNP rs139885151 (PrCa p-value 3e−13) and HIF1A 39 .…”