Abstract PR15: SUZ12: A novel tumor suppressor and potential biomarker for efficacy of BRD4 inhibition
Authors: Raedt Thomas De , Beert Eline , Pasmant Eric , Bradner James E. , Wolkenstein Pierre , Legius Eric , Cichowski Karen 
Published: August 2014

Patients with the familial cancer syndrome neurofibromatosis type I possess mutations in the NF1 tumor suppressor gene, which encodes a RasGAP. However a subset of patients carry a larger deletion that encompasses NF1 and the surrounding 13 genes. These patients develop hundreds of benign nervous system tumors, are at much higher risk for developing malignancies, and exhibit specific developmental defects. Therefore we hypothesized that a cooperating tumor suppressor must lie within this region. Notably, this entire region is frequently deleted in in a number of different cancers, including glioblastoma (GBM).

To identify a potential cooperating tumor suppressor we analyzed a large number of NF1-associated malignancies by array CGH and detected homozygous loss of SUZ12, a member of the PRC2 repressor complex. Subsequent mutation analysis showed that SUZ12 was homozygously inactivated in a large subset of MPNSTs. Importantly, reintroduction of SUZ12 in SUZ12 deficient Malignant Peripheral Nerve Sheath tumors (MPNST) cell lines restored the function of the PRC2 complex and induced cell death. Conversely, RNAi mediated inactivation of SUZ12 significantly enhanced the tumorigenic properties of NF1-deficient GBMs. Additionally, we found that mice carrying compound heterozygous mutations in Nf1 and Suz12 developed a variety of tumor types and had a marked decrease in overall survival.

As expected, knockdown of SUZ12 dramatically decreased the global H3K27 tri-methylation (repressive mark) and increased the global H3K27 acetylation (activation mark). This suggests that the pathogenic effect of SUZ12-loss is, at least in part, caused by an aberrant activation of genes due to an increase in H3K27 acetylation. Interestingly this H3K27 acetylation mark is read by BRD4, suggesting that inhibition of BRD4 might decrease the expression of critical targets. In vitro and in vivo studies indeed confirmed a hypersensitivity to BRD4 inhibition of cell lines and primary tumors lacking SUZ12. Additionally our preliminary data show an inverse correlation between the H3K27 tri-methylation level and the response to treatment with the BRD4 inhibitor JQ1, suggesting that SUZ12 levels, and thus H3K27 tri-methylation status, could be used as a biomarker.

In conclusion, we showed that SUZ12 is a tumor suppressor in a number of different cancers, including MPNSTs and gliomas. These tumors are exquisitely sensitive to inhibition of BRD4. Loss of SUZ12 leads to complete ablation of the H3K27 tri-methylation mark, which could serve as a biomarker for treatment with the BRD4 inhibitor JQ1.

This abstract is also presented as Poster B51.

Citation Format: Thomas De Raedt, Eline Beert, Eric Pasmant, James E. Bradner, Pierre Wolkenstein, Eric Legius, Karen Cichowski. SUZ12: A novel tumor suppressor and potential biomarker for efficacy of BRD4 inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR15.