Abstract A61: Hexim-1 protein expression levels modulate TGFβ activity in prostate cancer

Abstract

Abstract Hexim-1 is a highly conserved protein from human to mouse, and a well-established inhibitor of RNA polymerase II-dependent transcription elongation and cell proliferation. Others and we have proposed and provided evidence that changes in the expression and activity in Hexim-1 significantly influence the progression of cancer. Here we show that changes in expression levels of Hexim-1 modulate TGFβ1 signaling by inducing posttranslational modifications in the SMADs proteins (small mother against decapentaplegic) at the polylinker region of the Smad1 and Smad3 proteins. Cdk9 serine activity not only targets specific serine residues in the carboxyl terminus of RNA polymerase II during transcriptional elongation but also serine residues in the polylinker region of Smad3. Hexim-1 directly inhibits Cdk9 activity, and therefore, transcription elongation and TGFβ1/Smad3 activity. Our results indicate that prostate cancer accompanies significant changes in Hexim-1 expression as well as sub cellular redistribution. Similar observations were obtained in the TRAMP mouse model of prostate cancer. In order to understand the role of Hexim-1 during prostate cancer progression, we generated a TRAMP mouse model heterozygous for Hexim-1. Our studies in the TRAMP mouse model revealed that lowered levels in Hexim-1 protein expression triggered a more aggressive form of prostate cancer. TGFβ1/Smad3 plays a significant role during proliferation, cell migration, as well as in epithelial mesenchymal transition, which is critical during metastasis. To test the role of Hexim-1 as a modulator of TGF/Smad3 in vitro, we use the epithelial mouse prostate cancer cell line TRAMP-C2 and derived the TRAMP-C2 heterozygous for Hexim-1 (HT). We observed increased serine 208 phosphorylation of Smad3 as well as enhanced transcriptional activity of TGF β/Smad3 target genes involved in EMT such as SM22alpha and alpha smooth muscle actin in the HT-TRAMP-C2 cell line. These findings suggest that Hexim-1 is a critical regulator of prostate cancer progression. Citation Format: Manya Dhar-Mascareno, Eduardo Mascareno, Fang Liu. Hexim-1 protein expression levels modulate TGFβ activity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A61.