SAHA-induced loss of 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 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: ThrbPV/PV and ThrbPV/PVPten+/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 ThrbPV/PV mice, indicative of resistance to SAHA. Unexpectedly, thyroid cancer progressed in SAHAtreated ThrbPV/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 ThrbPV/PVPten+/mice, resulting in the activated effectors, p-Rb, CDK6, p21Cip1, 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 ThrbPV/PVPten+/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.