The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53-deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5-Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers.

中文翻译：

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含Pleckstrin同源结构域的蛋白质PHLDB3通过涉及p53的负反馈回路支持癌症的生长。

肿瘤抑制因子p53激活其靶基因的表达以发挥其功能。在这里，我们确定包含pleckstrin同源域蛋白（PHLDB3）编码基因作为p53目标。PHLDB3的过表达通过降低p53蛋白的水平来增加野生型p53癌细胞的增殖并抑制其凋亡。PHLDB3与MDM2（小鼠双分钟2同源物）结合，并促进MDM2介导的p53泛素化和降解。与缺乏p53的HCT116细胞相比，敲低PHLDB3可以更有效地抑制源自含有野生型p53的人结肠癌HCT116细胞的小鼠异种移植肿瘤的生长，并且还可以使肿瘤细胞对阿霉素和5-氟尿嘧啶敏感。癌症基因组数据库的分析表明，PHLDB3在许多人类癌症中均被扩增和/或高度表达。