Trim24 (Tif1α): An essential ‘brake’ for retinoic acid-induced transcription to prevent liver cancer

Abstract

N O T D I S T R I B U T E .Retinoic acid (RA), the active derivative of vitamin A, is an important signaling molecule that controls various developmental processes and influence the proliferation and differentiation of a variety of cell types. RA exerts its biological functions primarily through binding to and activating nuclear RA receptors (RARs, which include the RARa, b and g isotypes RARA, RARB and RARC). Aberrant expression or impaired function of these nuclear receptors has been linked to diverse types of cancer. RARs are RA-dependent transcription factors that regulate gene expression through the recruitment of different co-regulators (co-activators and co-repressors). TRIM24 (formerly known as TIF1a) was among the first co-regulators identified as interacting with RARs in a ligand-dependent fashion, and it was recently shown to function in mice as a potent liver-specific tumor suppressor by attenuating Rara-mediated transcription. The fact that Trim24 -/-, but not Trim24 -/-Rara +/-, mutant mice are highly predisposed to the development of hepatocellular carcinoma (HCC) has significant implications in cancer research. This result, along with the observation that in response to pharmacological inhibition of the RA signaling, hepatocytes lacking Trim24 loose their ability to proliferate, strongly implicates Rara as a proto-oncogene in hepatocytes and demonstrates that overactivated RA signaling is deleterious to liver homeostasis.

Prognostic Significance of TRIM24/TIF-1α Gene Expression in Breast Cancer

“…26 This liver specific effect (together with the association with prognosis and survival that we evidenced in the present study) may be linked to the p53 E3-ubiquitin ligase activity of TRIM24/TIF-1␣. Indeed, the overexpression of TRIM24/ TIF-1␣ in breast cancer may negatively regulate p53 levels and lead to increased tumorigenesis.…”

“…The TRIM24/TIF-1␣ gene might play an important role in tumorigenesis because it encodes a protein that controls nuclear receptor ligand-dependent activity 4,26 and also acts as a ubiquitin E3-ligase for the tumor suppressor p53. 10 In this study, we investigated the expression of TRIM24/TIF-1␣ in breast cancer at the mRNA, genomic, and protein levels.…”

Transcriptional co-factors and hepatic energy metabolism

“…In liver it has been described by Khetchoumian et al (2007Khetchoumian et al ( , 2008) that TRIM24 functioned as a tumor suppressor gene by attenuating RAR-alpha (retinoic acid receptor isotype alpha) dependent gene transcription as TRIM24 knockout mice showed a high incidence for the development of hepatocellular carcinoma [151,152].…”

Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma

“…TRIM24 was also identified in murine HCC as a fusion partner of BRAF in the chimeric oncoprotein T18 (6). Despite the fact that TRIM24 is widely expressed, Trim24 −∕− mice develop tumors only in the liver, showing that TRIM24 is a key suppressor of the initiation and development of hepatocarcinogenesis (7).…”