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 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 selectively upon Myc hyper-activation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent-Myc-switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for Myc-dependent tumor growth, and patient survival significantly correlates with SAE1/SAE2 levels in Myc-high tumors. These studies reveal a mitotic vulnerability of Myc-driven cancers, demonstrate that inhibiting sumoylation impairs Myc-dependent tumorigenesis, and suggest inhibiting SUMOylation may have therapeutic benefits for patients with Myc-driven cancer.

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

“…Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24)(25)(26)(27)(28)(29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17).…”

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

“…RNAi technology enables a systematic interrogation of genes whose loss of function affects cell proliferation and viability (Ashworth and Bernards 2010;Kessler et al 2012;Kumar et al 2012). While a powerful method for identifying novel therapeutic targets, genome-wide RNAi screens can be laborious and expensive, requiring substantial infrastructure and specialized expertise for their execution.…”

Upregulated Myc Expression in N-Methyl Nitrosourea (MNU)-induced Rat Mammary Tumours

“…Transformation by Myc depends on several additional protein-protein interactions, besides the interaction with Max protein (Oster et al, 2002). Kessler et al provided insight into how Myc's oncogenic activity might be suppressed by suppressing non-oncogenic proteins whose functions help Myc to transform cells (Kessler et al, 2012). So far, a considerable attention has been paid to the human breast cancer cell lines and mouse mammary tumour models for modelling human breast cancer, despite the fact that cell lines do not represent true tissue environment and, the majority of the mouse lesions are alveolar, while in humans and rats they are predominantly ductal (Thompson et al, 1985).…”

“…An unusual property of Myc gene is that the antisense strand of the gene also yields transcripts (Spicer and Sonenshein, 1992), which needs to be considered while designing RNAi strategies against Myc. Nevertheless, Myc inactivation or blocking strategies to combat various cancers have shown encouraging results in vitro (Wang et al, 2005;Hongxing et al, 2008;Zhang et al, 2009;Kessler et al, 2012), and in vivo models (Jain et al, 2002;Shachaf et al, 2004;Wang et al, 2005;Zhang et al, 2009). Soucek and Evan (2010) concluded in their review of Myc biology that systemic Myc inhibition is possible without affecting homeostasis in normal resting and proliferating tissues, and Myc is a supreme choice of cancer therapeutic target.…”

“…It is believed that tumours remain dependant or addicted to the activities of oncogenic pathways that drive tumorigenesis (Luo et al, 2009). However, many oncogenes such as Ras and Myc have proven difficult to be inhibited pharmacologically, highlighting the need for complementary approaches (Kessler et al, 2012). An unusual property of Myc gene is that the antisense strand of the gene also yields transcripts (Spicer and Sonenshein, 1992), which needs to be considered while designing RNAi strategies against Myc.…”