Unknown,Transcriptomics,Genomics,Proteomics

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A sumoylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis

ABSTRACT: Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we employed a genome-wide RNAi screen for Myc-synthetic-lethal (MySL) genes and uncovered a role for the SUMO-activating-enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc-switchers (SMS genes) governs mitotic spindle function and is required to support the Myc oncogenic program. comparison of 4 treatments: normal HMEC, High Myc in HMEC, SUMO depleted in HMEC, High Myc+Sumo Depleted in HMEC

ORGANISM(S): Homo sapiens

SUBMITTER: Chad Shaw

PROVIDER: E-GEOD-34055 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis.

Kessler Jessica D JD Kahle Kristopher T KT Sun Tingting T Meerbrey Kristen L KL Schlabach Michael R MR Schmitt Earlene M EM Skinner Samuel O SO Xu Qikai Q Li Mamie Z MZ Hartman Zachary C ZC Rao Mitchell M Yu Peng P Dominguez-Vidana Rocio R Liang Anthony C AC Solimini Nicole L NL Bernardi Ronald J RJ Yu Bing B Hsu Tiffany T Golding Ido I Luo Ji J Osborne C Kent CK Creighton Chad J CJ Hilsenbeck Susan G SG Schiff Rachel R Shaw Chad A CA Elledge Stephen J SJ Westbrook Thomas F TF

Science (New York, N.Y.) 20111208 6066

Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search for Myc-synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a tran ...[more]

PMID: 22157079

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Project description:Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress. Immortalized human mammary epithelial cells were infected with retrovirus expressing H-RASV12 with or without a retrovirus expressing ZEB1.

Dataset Information

A sumoylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis

Publications

A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis.

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