Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma

Liling Zeng, Ming Bai, Amit K. Mittal, Wassim El-Jouni, Jing Zhou, David M. Cohen, Mina I. Zhou, Herbert T. Cohen

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The von Hippel-Lindau (VHL) tumor suppressor pVHL is lost in the majority of clear-cell renal cell carcinomas (RCC). Activation of the PI3K/AKT/mTOR pathway is also common in RCC, with PTEN loss occurring in approximately 30% of the cases, but other mechanisms responsible for activating AKT at a wider level in this setting are undefined. Plant homeodomain protein Jade-1 (PHF17) is a candidate renal tumor suppressor stabilized by pVHL. Here, using kinase arrays, we identified phospho-AKT1 as an important target of Jade-1. Overexpressing or silencing Jade-1 in RCC cells increased or decreased levels of endogenous phospho-AKT/AKT1. Furthermore, reintroducing pVHL into RCC cells increased endogenous Jade-1 and suppressed endogenous levels of phospho-AKT, which colocalized with and bound to Jade-1. The N-terminus of Jade-1 bound both the catalytic domain and the C-terminal regulatory tail of AKT, suggesting a mechanism through which Jade-1 inhibited AKT kinase activity. Intriguingly, RCC precursor cells where Jade-1 was silenced exhibited an increased capacity for AKT-dependent anchorage-independent growth, in support of a tumor suppressor function for Jade-1 in RCC. In support of this concept, an in silico expression analysis suggested that reduced Jade-1 expression is a poor prognostic factor in clear-cell RCC that is associated with activation of an AKT1 target gene signature. Taken together, our results identify 2 mechanisms for Jade-1 fine control of AKT/AKT1 in RCC, through loss of pVHL, which decreases Jade-1 protein, or through attenuation in Jade-1 expression. These findings help explain the pathologic cooperativity in clear-cell RCC between PTEN inactivation and pVHL loss, which leads to decreased Jade-1 levels that superactivate AKT. In addition, they prompt further investigation of Jade-1 as a candidate biomarker and tumor suppressor in clear-cell RCC.

Original languageEnglish (US)
Pages (from-to)5371-5380
Number of pages10
JournalCancer Research
Volume73
Issue number17
DOIs
StatePublished - Sep 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zeng, L., Bai, M., Mittal, A. K., El-Jouni, W., Zhou, J., Cohen, D. M., Zhou, M. I., & Cohen, H. T. (2013). Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. Cancer Research, 73(17), 5371-5380. https://doi.org/10.1158/0008-5472.CAN-12-4707