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SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells

Xiaoliang L Xu1,2,3,4,5, Zhengke Li6,7, Aihong Liu2

  • 1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Cancer Research
|October 4, 2017
PubMed

Insights

Loss of RB1 protein function predisposes to tumors. Thyroid hormone receptor beta 2 (TRβ2) promotes RB1-deficient tumors by inhibiting the tumor-suppressive TRβ1, disrupting a natural safeguard.

Area of Science:

  • Molecular oncology
  • Cancer genetics
  • Endocrinology

Background:

  • Germline RB1 mutations are linked to retinoblastoma and pituitary tumors.
  • The specific molecular mechanisms sensitizing diverse cell types to RB1 loss remain unclear.
  • Thyroid hormone receptor beta (TRβ) isoforms, TRβ1 and TRβ2, play critical roles in cellular regulation.

Purpose of the Study:

  • To identify shared cell type-specific circuitry underlying RB1-deficient tumorigenesis.
  • To investigate the role of thyroid hormone receptor beta isoforms in RB1 loss-associated cancers.

Main Methods:

  • Analysis of RB1 mutations in human and mouse models.
  • Investigated the interaction between TRβ1, TRβ2, and SKP2 expression.
  • Utilized neuroblastoma cell lines to study RB1 and TRβ2 functions.

Main Results:

  • Thyroid hormone receptor beta 2 (TRβ2) sensitizes cells to RB1 loss by antagonizing TRβ1.
  • TRβ2 promotes SKP2 expression, a key factor in RB1-mutant tumors, by inhibiting its degradation.
  • RB1 loss normally allows TRβ1 to suppress SKP2, acting as a tumor safeguard, which TRβ2 disrupts.

Conclusions:

  • TRβ2 counteracts the tumor-suppressive TRβ1, disabling a safeguard against RB1-deficient tumorigenesis.
  • TRβ2 actively promotes the development of RB1-deficient malignancies by sustaining SKP2 levels.
  • Targeting the TRβ2/TRβ1 axis may offer therapeutic strategies for RB1-deficient cancers.

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