A histone deacetylase inhibitor promotes thyroid tumor progression in mouse models

Authors

• X Zhu
• DW Kim
• MC Willingham
• SY Cheng

Abstract

Thyroid cancer is the most common malignancy of endocrine organs. While the prognosis is excellent for most differentiated thyroid cancer, treatment modalities are limited for invasive and dedifferentiated thyroid cancer. New therapeutics is actively sought for treatment of metastatic dedifferentiated thyroid cancer. Histone deacetylases (HDACs) regulate the expression of genes critical for cancer initiation and cancer progression. Suberoylanilide hydroxyamic acid (SAHA) is a HDAC inhibitor approved for treatment of hematologic malignancies and is being explored for treatment of solid tumors. Here we evaluated the effects of SAHA on tumor growth in spontaneous metastatic thyroid cancer models (ThrbPV/PV and ThrbPV/PVPten+/− mice). Thyroid tumor growth of ThrbPV/PV mice was not affected by SAHA treatment. Intriguingly, thyroid tumor growth of ThrbPV/PVPten+/− mice was increased by SAHA treatment. Histopathological examination showed that SAHA accelerated vascular invasion, anaplasia formation and distant lung metastasis in ThrbPV/PVPten+/− mice. Molecular analysis showed that SAHA activated PI3K-AKT signaling pathway, resulting in the activation of its down effectors, p-RB, CDK4, CDK6, MMP2, MMP7 and increased ERBB2 to promote tumor growth. In thyroid tumors, PTEN protein abundance and Pten mRNA levels were significantly reduced after the treatment of ThrbPV/PVPten+/− mice with SAHA. Single molecule DNA analysis indicated that the remaining wild-type allele of Pten gene was progressively lost while thyroid tumors progressed in SAHA-treated ThrbPV/PVPten+/− mice. These findings suggest that Pten loss is critical in the development of resistance to SAHA and that effectors of Pten loss-activated pathways may be potential targets to overcome resistance to SAHA in thyroid cancer.

Scientific Focus Area: Cancer Biology

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