HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

Abstract

High mobility group A2 (HMGA2) is an architectural transcription factor that promotes human colorectal cancer (CRC) aggressiveness by modulating the transcription of target genes. The degradation of p53 is mediated by murine double minute 2 (MDM2) in a proteasome-dependent manner. Here we report that HMGA2 promotes cell cycle progression and inhibits apoptosis in CRC cells in vitro. We also developed an intestinal epithelial cell-specific Hmga2 knock-in (KI) mouse model. It revealed that the Hmga2 KI promoted chemical carcinogen-induced tumorigenesis in the intestine in vivo. In studying the underlying molecular mechanism, we found that HMGA2 formed a protein complex with p53. The tetramerization domain of p53 (amino acids 294-393) and the three AT-hook domains (amino acids 1-83) of HMGA2 were responsible for their direct interaction. We also found that HMGA2 directly bound to MDM2 and the central acidic and zinc finger domains of MDM2 (amino acids 111-360) were required for interaction with HMGA2. Furthermore, our results indicated that HMGA2 promoted MDM2-mediated p53 ubiquitination and degradation. Interestingly, Hmga2 overexpression in Hmga2 KI mice resulted in an increase in the accumulation of ubiquitinated p53. In addition, in two large CRC cohorts, it was demonstrated that high HMGA2 expression was predictive of an adverse outcome in the p53-negative subgroup of CRC patients. In summary, our data have established for the first time a novel mechanism by which HMGA2 functions with p53 and MDM2 to promote CRC progression. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Emerging roles for HMGA2 in colorectal cancer

“…Studies have shown that HMGA2 has effects in cancer development via regulating various signaling pathways, such as MDM2/p53, IL11/STAT3, and Wnt/β-catenin pathways ( Fig. 1 ) [ 40 , [46] , [47] , [48] , [49] ].

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“…Deletion mapping studies demonstrated that the two (amino acids 1–73) or three AT-hook domains (amino acids 1–83) of HMGA2 and the central acidic and zinc finger domains of MDM2 (amino acids 111–360) were sufficient for their association. Our findings indicated that HMGA2 directly interacted with p53 and MDM2, thereby increasing MDM2-mediated p53 ubiquitination and subsequently decreasing p53 protein stability and expression [ 46 ].…”

ZCCHC10 suppresses lung cancer progression and cisplatin resistance by attenuating MDM2-mediated p53 ubiquitination and degradation

“…Many proteins have been found to regulate p53 stability by affecting the interaction between p53 and MDM2. For example, LACTB stabilizes the p53 protein by disrupting the p53-MDM2 interaction 9 ; HMGA2 directly interacts with both p53 and MDM2 to enhance MDM2-mediated p53 ubiquitination and degradation 11 .…”

3’ UTR-truncated HMGA2 overexpression induces non-malignant in vivo expansion of hematopoietic stem cells in non-human primates

“… 10 , 11 , 12 , 13 Chromosomal translocations with breakpoints in HMGA2 that eliminate the 3’ UTR let-7 miRNA binding sites cause multiple tumor types. 36 , 37 , 38 High expression of HMGA2 in cancers of epithelial origin associates with increased aggressiveness 39 , 40 and is seen in some leukemias. 41 Chromosomal translocation of HMGA2 has also been seen in two cases of paroxysmal nocturnal hemoglobinuria.…”