Editors' ChoiceCancer

Guardian gone wild

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Science Translational Medicine  07 Oct 2015:
Vol. 7, Issue 308, pp. 308ec172
DOI: 10.1126/scitranslmed.aad3629

The p53 tumor suppressor, nicknamed “guardian of the genome,” orchestrates the transcriptional response to DNA damage to arrest growth of injured cells. Cells whose genetic damage is irreparable are killed in a p53-dependent manner to prevent genomic instability and malignant transformation. Consequently, inactivation of p53 unleashes an avalanche of accumulating mutations, ultimately resulting in cancer. Cancers may also arise from gain-of-function (GOF) point mutations within p53, although it is not clear how single mutations can turn this mild-mannered tumor suppressor into a cancer-driving oncogene.

To solve this puzzle, Zhu et al. audited genome-wide DNA binding locations for wild-type p53 and several GOF p53 mutants. All cancer-associated point mutations redirected p53 from activating the DNA damage response toward promoting expression of histone methyltransferases, master regulators of chromatin structure. Importantly, these p53 mutants stimulated expression of MLL1 (mixed-lineage leukemia), the histone methyltransferase whose dysregulation causes aggressive childhood leukemia. Abnormal MLL1 activity opens chromatin and haphazardly boosts expression of multiple genes, instantly transforming the cellular landscape without any further genetic mutations.

Could MLL1 be responsible for the malignant phenotype of cells driven by mutant p53? Indeed, the authors discovered that silencing MLL1 reduced proliferation and tumor formation by cancer cells fueled by GOF p53 mutants but not tumor cells with normal or absent p53. Moreover, drugs attacking the MLL1-activating multiprotein COMPASS complex selectively killed cells harboring GOF p53 mutations, suggesting a possible pharmacological approach to the treatment of cancers bearing these mutations. Analysis of publicly available tumor databases revealed MLL1 activation in tumors with mutant p53, independently validating the functional connection between p53 point mutants and MLL1 activity.

Zhu et al. not only discovered how GOF mutations force p53 to activate the MLL1-dependent malignant transcriptional program but also demonstrated how silencing the key regulator, MLL1, shuts down this elaborate gene-activation assault. Their findings strongly suggest that precision medicine therapeutics originally developed to target MLL-driven leukemia may be effective against other cancers driven by the p53 guardian harboring activating mutations.

J. Zhu et al., Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 525, 206–211 (2015). [Abstract]

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