Thyroid cancer is on the rise. Novel approaches are needed to improve the outcome of patients with recurrent and advanced metastatic
thyroid cancers. FDA approval of
suberoylanilide hydroxamic acid (SAHA;
vorinostat), an inhibitor of
histone deacetylase, for the treatment of
hematological malignancies led to the clinical trials of
vorinostat for advanced
thyroid cancer. However, patients were resistant to
vorinostat treatment. To understand the molecular basis of resistance, we tested the efficacy of SAHA in two mouse models of metastatic
follicular thyroid cancer: Thrb(PV/PV) and Thrb(PV/PV)Pten(+/-) mice. In both,
thyroid cancer is driven by overactivation of PI3K-AKT signaling. However, the latter exhibit more aggressive
cancer progression due to haplodeficiency of the
tumor suppressor, the Pten gene. SAHA had no effects on
thyroid cancer progression in Thrb(PV/PV) mice, indicative of resistance to SAHA. Unexpectedly,
thyroid cancer progressed in SAHA-treated Thrb(PV/PV)Pten(+/-) mice with accelerated occurrence of vascular invasion, anaplastic foci, and lung
metastasis. Molecular analyses showed further activated PI3K-AKT in thyroid
tumors of SAHA-treated Thrb(PV/PV)Pten(+/-) mice, resulting in the activated effectors, p-Rb, CDK6, p21(Cip1), p-cSrc,
ezrin, and
matrix metalloproteinases, to increase proliferation and invasion of
tumor cells. Single-molecule
DNA analysis indicated that the wild-type allele of the Pten gene was progressively lost, whereas
carcinogenesis progressed in SAHA-treated Thrb(PV/PV)Pten(+/-) mice. Thus, this study has uncovered a novel mechanism by which SAHA-induced loss of the
tumor suppressor Pten gene to promote
thyroid cancer progression. Effectors downstream of the Pten loss-induced signaling may be potential targets to overcome resistance of
thyroid cancer to SAHA.