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Loss of IGFBP7 expression and persistent AKT activation contribute to SMARCB1/Snf5-mediated tumorigenesis

J Darr1, A Klochendler1, S Isaac1

  • 1Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Oncogene
|July 16, 2013
PubMed

Insights

Loss of the SMARCB1 tumor suppressor reactivates AKT signaling, promoting aggressive pediatric tumors. Restoring SMARCB1 or inhibiting AKT halts tumor growth and restores cell death sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • SMARCB1 (Snf5/Ini1/Baf47) is a crucial tumor suppressor, and its loss is characteristic of aggressive pediatric neoplasms like malignant rhabdoid tumors (MRT) and atypical teratoid/rhabdoid tumors (AT/RT).
  • SMARCB1 is a core component of Swi/Snf chromatin remodeling complexes, implicated in various cancers when its function is compromised.

Purpose of the Study:

  • To investigate the functional consequences of SMARCB1 restoration in Smarcb1-deficient tumor cells.
  • To elucidate the molecular mechanisms underlying SMARCB1-mediated tumor suppression, focusing on signaling pathways and gene expression.
  • To identify potential therapeutic targets for Smarcb1-deficient tumors.

Main Methods:

  • Restoration of Smarcb1 expression in Smarcb1-deficient murine tumor cells.
  • Assessment of tumor cell sensitivity to programmed cell death and xenograft growth.
  • Analysis of AKT and PI3K signaling pathways.
  • In vitro and in vivo evaluation of AKT inhibition efficacy.
  • Profiling of Smarcb1-dependent gene expression.

Main Results:

  • Re-introduction of Smarcb1 restored sensitivity to programmed cell death and abolished xenograft tumor growth, without inducing growth arrest.
  • Persistent AKT signaling activation was observed in Smarcb1-deficient cells, contributing to tumor cell survival and proliferation.
  • AKT inhibition effectively suppressed proliferation of Smarcb1-deficient cells in vitro and inhibited xenograft tumor development in vivo.
  • SmarcB1 is essential for the expression of genes involved in extracellular matrix and cell adhesion.
  • SmarcB1 is required for the transcriptional activation of the tumor suppressor Igfbp7, and its re-introduction alone inhibited tumor development.

Conclusions:

  • Loss of SMARCB1 promotes tumorigenesis through mechanisms involving AKT signaling activation and altered gene expression.
  • Restoring SMARCB1 function or inhibiting AKT signaling represents a promising therapeutic strategy for Smarcb1-deficient tumors.
  • Igfbp7 is a key downstream effector of SMARCB1 tumor suppression, highlighting its potential as a therapeutic target.

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