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SAHA-induced loss of tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model

Xuguang Zhu1, Dong Wook Kim1, Li Zhao1

  • 1Laboratory of Molecular BiologyCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Endocrine-Related Cancer
|June 9, 2016
PubMed

Insights

Histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) unexpectedly accelerated thyroid cancer progression in mice by inducing loss of the Pten tumor suppressor gene. This finding reveals a novel resistance mechanism and potential therapeutic targets for advanced thyroid cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Thyroid cancer incidence is increasing, necessitating new treatments for advanced and recurrent disease.
  • Suberoylanilide hydroxamic acid (SAHA; vorinostat), a histone deacetylase inhibitor, showed limited efficacy in clinical trials for advanced thyroid cancer due to patient resistance.
  • PI3K-AKT signaling pathway overactivation drives thyroid cancer, particularly in models with Pten tumor suppressor gene alterations.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying resistance to SAHA in metastatic thyroid cancer.
  • To evaluate the efficacy of SAHA in mouse models of metastatic follicular thyroid cancer with varying Pten gene status.
  • To identify potential therapeutic targets to overcome SAHA resistance in thyroid cancer.

Main Methods:

  • Utilized two mouse models of metastatic follicular thyroid cancer: Thrb(PV/PV) and Thrb(PV/PV)Pten(+/-).
  • Administered SAHA to mice and monitored tumor progression, metastasis, and molecular alterations.
  • Performed molecular analyses including PI3K-AKT signaling pathway assessment, cell proliferation, invasion markers, and single-molecule DNA analysis for Pten gene status.

Main Results:

  • SAHA demonstrated no effect on thyroid cancer progression in Thrb(PV/PV) mice, confirming resistance.
  • In SAHA-treated Thrb(PV/PV)Pten(+/-) mice, thyroid cancer progression was unexpectedly accelerated, with increased vascular invasion, anaplastic foci, and lung metastasis.
  • SAHA treatment led to further PI3K-AKT activation and increased expression of proliferation and invasion effectors (p-Rb, CDK6, p21(Cip1), p-cSrc, ezrin, MMPs) in Thrb(PV/PV)Pten(+/-) mice.
  • Progressive loss of the wild-type Pten allele was observed in SAHA-treated Thrb(PV/PV)Pten(+/-) mice, correlating with enhanced carcinogenesis.

Conclusions:

  • SAHA treatment can induce loss of the Pten tumor suppressor gene, promoting thyroid cancer progression and metastasis.
  • This study uncovers a novel mechanism of SAHA resistance in thyroid cancer driven by Pten gene loss.
  • Targeting downstream effectors of Pten loss-induced signaling may offer strategies to overcome SAHA resistance in advanced thyroid cancer.
Keywords:
SAHAgenetically engineered mouse modelthyroid cancerthyroid hormone receptorstumor suppressor PTENtumorigenesisvorinostat

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