Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53

Tengfei Chao, Xiang Zhou, Bo Cao, Peng Liao, Hongbing Liu, Yun Chen, Hee-Won Park, Shelya X. Zeng and Hua Lu ()
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Tengfei Chao: Tulane University School of Medicine
Xiang Zhou: Tulane University School of Medicine
Bo Cao: Tulane University School of Medicine
Peng Liao: Tulane University School of Medicine
Hongbing Liu: Tulane University School of Medicine
Yun Chen: Tulane University School of Medicine
Hee-Won Park: Tulane University School of Medicine
Shelya X. Zeng: Tulane University School of Medicine
Hua Lu: Tulane University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13755

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