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INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas

Meng Na Chi1, Su Tang Guo2,3, James S Wilmott4

  • 1School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia.

Oncotarget
|November 18, 2015
PubMed

Insights

Inositol polyphosphate 4-phosphatase type II (INPP4B) drives melanoma by activating SGK3, not Akt. Restoring miR-494 and miR-599 may offer new melanoma treatment strategies targeting INPP4B.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Inositol polyphosphate 4-phosphatase type II (INPP4B) typically suppresses tumors by inhibiting PI3K/Akt signaling.
  • However, INPP4B is found to be upregulated in a subset of melanomas, suggesting a different role.

Purpose of the Study:

  • To investigate the oncogenic role of INPP4B in melanoma.
  • To elucidate the mechanism by which INPP4B promotes melanoma proliferation.
  • To explore the potential of targeting INPP4B and related miRNAs for melanoma treatment.

Main Methods:

  • Investigated INPP4B function via knockdown and overexpression in melanoma cells and melanocytes.
  • Analyzed the role of serum- and glucocorticoid-regulated kinase 3 (SGK3) in INPP4B-mediated proliferation.
  • Examined the association between INPP4B levels, miRNA (miR)-494/miR-599 expression, and gene copy number.
  • Assessed the effects of miR-494/miR-599 overexpression and inhibition on melanoma cell behavior.

Main Results:

  • INPP4B overexpression enhanced melanoma cell and melanocyte proliferation and triggered anchorage-independent growth.
  • INPP4B-driven proliferation was mediated by SGK3 activation, independent of Akt.
  • Upregulation of INPP4B correlated with reduced miR-494/miR-599 levels due to gene copy number reduction.
  • Restoring miR-494/miR-599 inhibited melanoma proliferation by downregulating INPP4B and SGK3.

Conclusions:

  • INPP4B acts as an oncogenic driver in a subset of melanomas through SGK3 activation.
  • Loss of miR-494 and miR-599 contributes to INPP4B upregulation and melanoma growth.
  • Targeting INPP4B and restoring miR-494/miR-599 represent potential therapeutic strategies for melanoma.
Keywords:
INPP4BSGK3melanomamiRNA-494miRNA-599

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