Targeting MDM4 as a Novel Therapeutic Approach for Hematologic Malignancies

Abstract

Mouse double minute 4 (MDM4) as a member of MDM family, is an oncogene emerging as an imperative negative regulator of p53. Tumor suppressor protein p53 plays a crucial role in cell cycle arrest, apoptosis and homeostasis. It has been reported that frequent inactivation of p53 was observed in numerous human cancers including hematologic malignancies. MDM4, the newly discovered modulator of p53 protein, is frequently amplified in various solid tumors such as cutaneous melanoma, retinoblastoma and hematological malignances such as chronic lymphocytic leukemia, acute myeloid leukemia and mantle cell lymphoma. Multiple evidences implicate that over-expression of MDM4 is associated with tumor progression and poor prognosis which can be reversed by knockdown of MDM4 expression or restoration of p53 function, and support the rationale for the design of future MDM4-specific therapeutics. This article discusses and focuses on using MDM4 as a novel biomarker as well as a therapeutic target for hematologic malignancies.

miR‐33a inhibits cell growth in renal cancer by downregulation of MDM4 expression

“…MDM4 can inhibit the function of P53 during a number of types of cancer for MDM4 shares an N-terminal p53-binding domain with MDM2 (OMIM 164,785) (Gansmo et al, 2015;Xu et al, 2016). The overexpression of MDM4 in a variety of tumors may be related to inhibition of the function of P53 and result in tumorigenesis, tumor progression, and metastasis (Bao et al, 2016;Cao et al, 2015;Marine & Jochemsen, 2016). Many studies reported the overexpression of MDM4 in prostate cancer, gastric cancer, hematologic malignancies, etc (Gansmo et al, 2015;Marine & Jochemsen, 2016;Miranda et al, 2017;Wang et al, 2016).…”

“…The activity of P53 is reduced by MDM4 overexpression, which contributes to tumorigenesis (Gansmo et al, ; Jeffreena Miranda et al, ). Furthermore, MDM4 is overexpressed in prostate cancer, gastric cancer, hematologic malignancies, lung cancer, etc (Bao, Song, Xu, Qu, & Xue, ; Cao, Xu, & Li, ; Gansmo et al, ; Marine & Jochemsen, ; Miranda et al, ; Xiong et al, ; Xu et al, ). Those studies demonstrated that MDM4 might be closely involved in tumorigenesis.…”