RbAp48 IS A TARGET OF NF-kB ACTIVITY IN THYROID CANCER.

Context: We have recently shown that nuclear factor (NF)-kB activity is constitutively elevated in anaplastic human thyroid carcinomas. The inhibition of NF-kB in the anaplastic thyroid carcinoma cell line (FRO) leads to increased susceptibility to apoptosis induced by chemotherapeutic drugs and to the block of oncogenic activity. Objectives: To understand better the molecular mechanisms played by NF-kB in thyroid oncogenesis, we performed a differential proteomic analysis between FRO transfected with a superrepressor form of inhibitor of kBalpha (IkBalphaM) and the parental counterpart (FRO Neo cells). Results: Differential proteomic analysis revealed that the retinoblastoma-associated protein 48 (RbAp48) is down-regulated in theabsence of functional NF-kB. Immunohistochemical analysis of normal and pathological human thyroid specimens confirmed that RbAp48 is strongly overexpressed in primary human carcinomas. Reduction of RbAp48 expression using small interfering RNA determined the suppression of tumorigenicity, very likely due to the decrease of their growth rate rather than to an increased susceptibility to apoptosis. In addition, we showed that NF-kB, at least in part, transcriptionally controls RbAp 48. A functional NF-kB consensus sequence was located within the promoter region of RbAp48 human gene, and embryonic fibroblasts isolated from the p65 knockout mouse (murine embryonic fibroblasts p65-/-) showed decreased expressionof RbAp48. Conclusion: Our results show that RbAp48 is a NF-kB-regulated gene playing an important role in thyroid cancer cell autonomousproliferation. (J Clin Endocrinol Metab 92: 1458-1466, 2007)