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

Abstract

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 hematologic 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 the resistance, we tested the efficacy of SAHA in two mouse models of metastatic follicular thyroid cancer: Thrb ^PV/PV and Thrb ^PV/PVPten ^+/− mice. In both, thyroid cancer is driven by over-activation of PI3K-AKT signaling. But 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/PVPten ^+/− 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/PVPten ^+/− 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 while carcinogenesis progressed in SAHA-treated Thrb ^PV/PVPten ^+/− mice. Thus, the present studies have uncovered a novel mechanism by which SAHA-induced loss of the tumor suppressor Pten 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.