Abstract 1403: TRIM16 inhibits cell growth through direct interaction and modulation of TDP43 protein stability in cancer cells

Abstract

Abstract The tripartite motif (TRIM) family of proteins are involved in a diverse range of cellular processes ranging from innate immunity, oncogenesis as well as tumor suppression. A majority of these reported functions occur through protein-protein interactions. Previously, we have found a strong correlation between loss of TRIM16 expression and disease progression in three human cancers: neuroblastoma, squamous cell carcinoma and melanoma. Moreover, our studies have shown that TRIM16 acts as a tumor suppressor in these cancers through effects on cell cycle and migration. In order to better understand the mechanism of TRIM16 in cancer cell growth inhibition, we have identified a novel binding partner of TRIM16 and investigated the functional outcome of the protein-protein interaction. Using the yeast two-hybrid screening tool, we identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein. TDP43 has been described as a RNA/DNA binding protein with a putative role in HIV transcription and reports also suggest that this protein plays a role in a wide range of neurodegenerative diseases. Through co-immunoprecipitation studies, we have demonstrated that TDP43 directly binds to TRIM16 in human BE(2)-C neuroblastoma and MCF7 breast cancer cells. Enforced over-expression of TRIM16 increased the protein half-life of TDP43. We have also shown that TDP43 expression was required for TRIM16 induced inhibition of neuroblastoma and breast cancer cell growth. Moreover, we have shown that two cell cycle regulatory proteins, E2F1 and pRb, were regulated by TRIM16 and TDP43. Taken together, our studies suggest that the novel mechanism by which TRIM16 inhibits cancer cell growth is through the direct interaction and up-regulation of TDP43 protein expression and with consequent effects on E2F1 and phos-Rb. Citation Format: Patrick Y. Kim, Owen Tan, Toby Trahair, Tao Liu, Glenn M. Marshall, Belamy B. Cheung. TRIM16 inhibits cell growth through direct interaction and modulation of TDP43 protein stability in cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1403. doi:10.1158/1538-7445.AM2014-1403