Abstract B17: TRIM24 links epigenetics and metabolism in cancer
Authors: Thakkar Kaushik N. , Jiang Shiming , Stratton Sabrina , Barton Michelle 
Published: May 2016

The TRIpartite Motif (TRIM) family of proteins has approximately 70 proteins, which are involved in a variety of processes, including regulation of protein stability, transcription, cell proliferation and apoptosis. Our laboratory discovered TRIM24, as an E3-ubiquitin ligase of p53, using embryonic stem cells and breast cancer cell lines as model systems. Earlier reports identified TRIM24 as a transcriptional co-regulator of nuclear receptor signaling, directly interacting with retinoic-acid receptor (RAR), thyroid receptor, androgen receptor and estrogen receptor (ER). Since our laboratory's initial report showing TRIM24 over expression correlates with poor survival of breast cancer patients, several studies reported roles of TRIM24 in multiple cancers such as NSLC, head and neck carcinoma, hepatocellular carcinoma, colorectal cancer and glioblastoma.

We found that TRIM24 expression is deregulated during breast cancer progression and likely early in the process. I found that the ectopic expression of TRIM24 in immortalized Human mammary epithelial cells (HMECs) greatly increased cellular proliferation and induced malignant transformation. Subcutaneous injection of TRIM24-HMECs in nude mice displayed significantly higher xenograft volume as compared to their control counterparts. Interestingly, molecular analysis of TRIM24-HMECs revealed a glycolytic and tricarboxylic acid cycle gene signature, alongside increased glucose uptake and activated aerobic glycolysis. Using Chromatin immunoprecipitation (ChIP), I saw TRIM24 binding at the promoters of several glycolytic and TCA cycle genes such as GLUT1, IDH1, IDH2 and c-Myc Consistent with in vitro findings, the Glucose transport pathway was among the top 10 pathways positively correlated with TRIM24 expression in human breast tumors (n = 1008) from the TCGA database. Thus, TRIM24 is co-expressed with genes that regulate glucose metabolism in breast tumors, supporting clinical relevance of our findings.

Mechanistically, we have previously reported that TRIM24 acts as a transcriptional co-regulator by “reading” a specific signature of histone post-translational modifications (H3K4me0-H3K23ac) via a tandem plant homeodomain (PHD) and bromodomain (Bromo) within the C-terminus of TRIM24. Additionally, TRIM24 via its RING domain acts as an E3-ubiquitin ligase of p53 and targets it for proteasome-mediated degradation. Currently, I am performing studies to determine if chromatin association of TRIM24 via the PHD/Bromo-domain and/or RING-domain activity is critical for oncogenic transformation linked with metabolic reprograming in cancer. In summary, our studies suggest a unique role for TRIM24 in early steps of mammary carcinogenesis that involves reprogramming of glucose metabolism and the results provide the groundwork to test chemical therapeutics that disrupt TRIM24 functions, e.g. Bromodomain inhibitors.

Citation Format: Kaushik N. Thakkar, Shiming Jiang, Sabrina Stratton, Michelle Barton. TRIM24 links epigenetics and metabolism in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B17.