Defining the MYC Transcriptional Regulatory Network in Human Cancer

Activation of the MYC oncogene is a principal molecular feature of tumorigenesis in human cancers. MYC primarily functions as a transcription factor that coordinates an extensive regulatory network of biological processes, including proliferation, metabolism, and apoptosis. When pathologically expressed, MYC drives tumor-intrinsic pathways that perpetuate neoplastic growth and silence the impetus for programmed cell death. While MYC is widely researched, the biochemical mechanisms by which it paradoxically induces either cell survival or cell death are not fully understood. Previously, we identified BAG1 as a target of MYC and a critical determinant of this cell fate decision. Multiple functions have been ascribed to BAG1, predominantly as a molecular chaperone responsible for proper protein folding/stability and as a transcriptional co-factor. These differing activities are controlled by distinct BAG1 protein isoforms. We report here that a single, unique isoform of BAG1, termed BAG1S, associates with heat shock protein HSP70 to enhance the survival of tumor cells with elevated MYC. To interrogate additional nodes within this pathway, a proteomics approach was used to identify a set of specific pro-survival clients mediated by the BAG1S/HSP70 complex. Collectively, these findings broaden our understanding of the biochemical events that MYC-driven tumor cells engage in order to survive. Survival of cancer cells is dependent on the sustained activation of oncogenic MYC. Despite this sensitivity, efforts to explicitly manipulate MYC function have been clinically unsuccessful. Here we identify tumor necrosis factor receptor superfamily member 8 (CD30/TNFRSF8) as a target of MYC. Elevated levels of CD30 are observed in many lymphoid malignancies, while expression is remarkably restricted in normal cells. Through a genetic and biochemical approach, we define CD30 induction in a MYC-dependent manner across a variety of human cell lines. Given its expression at the cell surface, CD30 has emerged as an important diagnostic marker and therapeutic target. Using the FDA-approved CD30 antibody-drug conjugate Brentuximab Vedotin (BV), we demonstrate that CD30-targeted therapies rely on MYC activity. Blocking MYC expression with the BET-inhibitor JQ1 significantly reduced the efficacy of BV, whereas inducing oncogenic levels of MYC dramatically increased susceptibility to BV. Taken together, these data establish a model in which MYC-induced expression of CD30 offers a new treatment avenue for MYC-driven cancers. MYC facilitates transcription by cooperating with co-factors and recruiting the fundamental chromatin remodeling complex SAGA. SAGA harbors two enzymatic modules that modify the acetylation and ubiquitylation of distinct histones to affect transcription. The ubiquitin protease USP22 is a catalytic subunit of the SAGA deubiquitylase module. Overexpression of USP22 bolsters cell cycle progression and drives aggressive cancer phenotypes. Current models suggest that USP22 mediates express biological effects via its bona fide function in epigenetic regulation. Here we report a non-transcriptional role, demonstrating that USP22 regulates the core cell cycle machinery by stabilizing the G1 cyclin, cyclin D1 (CCND1). Direct deubiquitylation of CCND1 protects it from proteasomal degradation and partially explains the mechanism by which USP22 mediates cell cycle progression. USP22 and CCND1 levels correlate in patient lung and colorectal cancer samples and our pre-clinical studies indicate that targeting USP22 in combination with CDK inhibitors may offer an approach for treating cancer patients whose tumors exhibit elevated CCND1