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 Cohen, Mina I. Zhou, Herbert T. Cohen

Research output: Contribution to journalArticle

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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

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Renal Cell Carcinoma
Neoplasms
Phosphotransferases
Homeodomain Proteins
Plant Proteins
Tumor Biomarkers
Phosphatidylinositol 3-Kinases
Computer Simulation
Catalytic Domain
Kidney
Growth
Genes
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. / Zeng, Liling; Bai, Ming; Mittal, Amit K.; El-Jouni, Wassim; Zhou, Jing; Cohen, David; Zhou, Mina I.; Cohen, Herbert T.

In: Cancer Research, Vol. 73, No. 17, 01.09.2013, p. 5371-5380.

Research output: Contribution to journalArticle

Zeng, L, Bai, M, Mittal, AK, El-Jouni, W, Zhou, J, Cohen, D, Zhou, MI & Cohen, HT 2013, 'Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma', Cancer Research, vol. 73, no. 17, pp. 5371-5380. https://doi.org/10.1158/0008-5472.CAN-12-4707
Zeng, Liling ; Bai, Ming ; Mittal, Amit K. ; El-Jouni, Wassim ; Zhou, Jing ; Cohen, David ; Zhou, Mina I. ; Cohen, Herbert T. / Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. In: Cancer Research. 2013 ; Vol. 73, No. 17. pp. 5371-5380.
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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.",
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AU - El-Jouni, Wassim

AU - Zhou, Jing

AU - Cohen, David

AU - Zhou, Mina I.

AU - Cohen, Herbert T.

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