MLL1 is essential for the senescence-associated secretory phenotype

Capell, B. C. et al. (2016) MLL1 is essential for the senescence-associated secretory phenotype. Genes and Development, 30(3), pp. 321-336. (doi: 10.1101/gad.271882.115) (PMID:26833731) (PMCID:PMC4743061)

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.

• Item Type: Articles
• Additional Information: This work was supported by Dermatology Foundation, American Skin Association, and Melanoma Research Foundation grants to B.C.C. as well as a National Institute on Aging P01 grant (P01AG031862) awarded to P.D.A. and S.L.B.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rai, Dr Taranjit and Adams, Professor Peter
• Authors: Capell, B. C., Drake, A. M., Zhu, J., Shah, P. P., Dou, Z., Dorsey, J., Simola, D. F., Donahue, G., Sammons, M., Rai, T., Natale, C., Ridky, T. W., Adams, P. D., and Berger, S. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Genes and Development
• Publisher: Cold Spring Harbor Laboratory Press
• ISSN: 0890-9369
• ISSN (Online): 1549-5477
• Copyright Holders: Copyright © 2016 Capell et al.
• First Published: First published in Genes and Development 30(3): 321-336
• Publisher Policy: Reproduced under a Creative Commons License