Mll1 is essential for the senescenceassociated secretory phenotype

Brian C. Capell, Adam M. Drake, Jiajun Zhu, Parisha P. Shah, Zhixun Dou, Jean Dorsey, Daniel F. Simola, Greg Donahue, Morgan Sammons, Taranjit Singh Rai, Christopher Natale, Todd W. Ridky, Peter D. Adams, Shelley L. Berger

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59 Citations (Scopus)

Abstract

Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces “SASP-like” inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression.

Original languageEnglish
Pages (from-to)321-336
Number of pages16
JournalGenes and Development
Volume30
Issue number3
DOIs
Publication statusPublished - 1 Feb 2016

Keywords

  • DNA damage response
  • Epigenetic
  • Inflammation
  • MLL1
  • Oncogene-induced senescence
  • Senescence-associated secretory phenotype

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    Capell, B. C., Drake, A. M., Zhu, J., Shah, P. P., Dou, Z., Dorsey, J., Simola, D. F., Donahue, G., Sammons, M., Rai, T. S., Natale, C., Ridky, T. W., Adams, P. D., & Berger, S. L. (2016). Mll1 is essential for the senescenceassociated secretory phenotype. Genes and Development, 30(3), 321-336. https://doi.org/10.1101/gad.271882.115