Tumour suppressors: Keeping Trim

signaling update home

SOURCE:

Tripartate motif-containing 24 (Trim24) appears to restrict the genesis of hepatocellular carcinoma (HCC) by inhibiting the retinoic acid (RA) transcriptional network.

Hepatocellular carcinoma (HCC), a relatively common cancer worldwide, can be induced by many different stimuli. Régine Losson and colleagues have found that in mice one tumour-suppressor gene, tripartate motif-containing 24 (Trim24), seems to specifically restrict the genesis of HCC through regulating the retinoic acid (RA) transcriptional network.

RA binds to a number of receptors that form part of the nuclear receptor superfamily and control transcription by recruiting a number of co-regulatory proteins. One such protein is TRIM24, which can act as either a positive or negative regulator of transcription. Losson and colleagues produced Trim24-knockout mice to further examine its function. These mice developed normally and showed no signs of illness before 2 months of age. However, long-term analyses of a large colony (100) of Trim24-null mice showed that 80% of males and 69% of females between 9 and 29 months of age developed liver tumours.

Hepatocytes remain proliferative during the neonatal period, but undergo quiescence soon after birth. Analyses of hepatocyte proliferation using Ki67 staining indicated that although wild-type livers showed reduced levels of Ki67 staining by 3 weeks of age, livers from Trim24-null mice did not show such a marked reduction in hepatocyte proliferation, indicating that loss of Trim24 prohibits cell-cycle exit. Consistent with this finding, overexpression of Trim24 in hepatocytes induced cell-cycle arrest.

Having established the biological function of TRIM24 in hepatocytes, the authors then addressed whether loss of Trim24 affected RA signalling pathways. Addition of RA to mouse embryonic fibroblasts (MEFs) from both wild-type and Trim24-null mice showed that RA responsive genes (such as Cyp26a1, Tgm2 and Crbp1) were more highly expressed in Trim24-null MEFs, and that a tagged form of TRIM24 was present on the RA-responsive elements in Cyp26a1 in HepG2 cells. Both of these results are consistent with an inhibitory function for TRIM24 in RA-dependent transcription.

To induce transcription, RA binds to RA receptors (RAR) alpha , beta and gamma , and the authors showed that the reduction in the expression levels of RAR alpha seen in Trim24^-/-;Rara^+/- mice was enough to suppress liver tumour formation, indicating that Rara is haploinsufficient for tumorigenesis in Trim24-null mice. In agreement with this, the expression of RA-target genes is deregulated in Trim24-null mice, and this seems to be dependent on RAR alpha expression — no significant changes in RA-dependent gene expression were evident in livers from Trim24^-/-;Rara^+/- mice.

These results might explain why overexpression of RARA is evident in human HCC and they also indicate that the use of RAR alpha agonists in cancer therapy should proceed with caution.

Nicola McCarthy

References

Khetchoumian, K. et al. Loss of Trim24 (Tif1) gene function confers oncogenic activity to retinoic acid receptor . Nature Genet. 39, 1500–1506 (2007) | Article | PubMed |