Abstract B60: Identification of the specific histone deacetylases involved in the silencing of transforming growth factor β receptor II in colon cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-07, Vol.73 (13_Supplement), p.B60-B60
• Main Authors: Murari, Catherine, Howell, Gillian M., Brattain, Michael G.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.CEC13-B60

Colorectal cancer is the 3rd leading cause of cancer deaths in the United States. Activation of oncogenes and silencing of tumor suppressor genes (TSG) contribute to the development and progression of colorectal cancer. One such TSG is the transforming growth factor β receptor II (TGFβRII) which results in loss of growth inhibitory TGFβ signaling and is a common event in cancer progression. Although mutation of this TSG is common, especially in tumors which exhibit microsatellite instability there is increasing evidence that TGFβRII is epigenetically silenced in many different cancers. Restoration of TGFβ signaling by re-introduction of TGFβRII results in anti-cancer effects in colon and other cancer cell lines. Histone deacetylases (HDACs) are involved in the mechanism of epigenetic silencing. These enzymes remove the acetyl groups from lysine tails of histones usually resulting in gene repression. HDACs are classified into 4 groups (Classes I, IIa, IIb, III and IV) and, except for Class III, need the zinc cation for their function. Deacetylation by Class III HDACs (Sirtuins) is NAD+ mediated. Histone deacetylase inhibitors (HDACi) have recently entered clinical trials and are effective in inhibiting growth and inducing apoptosis in many hematological malignancies but results against solid tumors as single therapies has been disappointing. A significant effect of these drugs is reactivation of TSGs via histone deacetylation inhibition which results in alterations in the chromatin permitting transcription of these silenced genes. Our laboratory has previously demonstrated that the pan HDACi Belinostat, which inhibits Class I and II HDACs, effectively induced TGFβRII expression in cancer cell lines with epigenetically silenced receptor restoring TGFβ downstream signaling effects including the TGFβ dependent decrease in survivin. Therefore, HDACi provide a potential therapy to restore the growth inhibitory and apoptotic effects of the TGFβ inhibitory pathway. We hypothesize that the identification of the specific HDACs involved in reactivation of epigenetically silenced TGFβRII would allow the use of more specific HDACis which would increase the therapeutic index of these drugs, decrease side effects and permit more effective use in combination therapies. We are using both genetic and pharmacological approaches to identify the specific HDACs involved in reactivation of TGFβRII. We have performed lentiviral shRNA knockdown of HDAC1, 2 and 3 and observed that