Aimee T. Farria

Overexpression of the MYC oncoprotein is an initiating step in the formation of several cancers. MYC frequently recruits chromatin-modifying complexes to DNA to amplify the expression of cancer-promoting genes, including those regulating cell cycle, proliferation, and metabolism, yet the roles of specific modifiers in different cancer types are not well defined. Here, we show that GCN5 is an essential coactivator of cell-cycle gene expression driven by MYC overexpression and that deletion of Gcn5 delays or abrogates tumorigenesis in the Eμ-Myc mouse model of B-cell lymphoma. Our results demonstrate that Gcn5 loss impacts both expression and downstream functions of Myc.Significance:Our results provide important proof of principle for Gcn5 functions in formation and progression of Myc-driven cancers, suggesting that GCN5 may be a viable target for development of new cancer therapies.

Supple Table 1 DAVID GO pathways Suppl Table 2 EGFR Down regulated genes Suppl Table 3 Hgf Down regulated genes Suppl Tab 4 VEGF down regulated genes Suppl Table 5 Antibodies used Suppl Table 6 Primers used

Suppl figs 1-4: Suppl fig 1 Flow cytometry data, B cells Suppl Fig 2 qRT PCR plasmabalst genes Suppl Fig 3 Flow Cytometry Prelymphomic B cells Suppl Fig 4 RNA seq analyses

Suppl figs 1-4: Suppl fig 1 Flow cytometry data, B cells Suppl Fig 2 qRT PCR plasmabalst genes Suppl Fig 3 Flow Cytometry Prelymphomic B cells Suppl Fig 4 RNA seq analyses

Supple Table 1 DAVID GO pathways Suppl Table 2 EGFR Down regulated genes Suppl Table 3 Hgf Down regulated genes Suppl Tab 4 VEGF down regulated genes Suppl Table 5 Antibodies used Suppl Table 6 Primers used

Overexpression of the MYC oncoprotein is an initiating step in the formation of several cancers. MYC frequently recruits chromatin-modifying complexes to DNA to amplify the expression of cancer-promoting genes, including those regulating cell cycle, proliferation, and metabolism, yet the roles of specific modifiers in different cancer types are not well defined. Here, we show that GCN5 is an essential coactivator of cell-cycle gene expression driven by MYC overexpression and that deletion of Gcn5 delays or abrogates tumorigenesis in the Eμ-Myc mouse model of B-cell lymphoma. Our results demonstrate that Gcn5 loss impacts both expression and downstream functions of Myc.Significance:Our results provide important proof of principle for Gcn5 functions in formation and progression of Myc-driven cancers, suggesting that GCN5 may be a viable target for development of new cancer therapies.

Acetyl-CoA is a central metabolite used for lipid synthesis in the cytosol and histone acetylation in the nucleus, among other pathways. The two major precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. While some evidence has suggested the existence of additional routes to nuclear-cytosolic acetyl-CoA, such pathways remain poorly defined. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2. Unexpectedly, and in contrast to observations in fibroblasts, ACLY and ACSS2 double knockout (DKO) cancer cells remain viable and proliferate, maintain pools of cytosolic acetyl-CoA, and are competent to acetylate proteins in both cytosolic and nuclear compartments. Using stable isotope tracing, we show that both glucose and fatty acids feed acetyl-CoA pools and histone acetylation in DKO cells. Moreover, we provide evidence for the carnitine shuttle and carnitine acetyltransferase (CrAT) as a substantial pathway to transfer two-carbon units from mitochondria to cytosol independent of ACLY. Indeed, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and CrAT-dependent manner. This work defines a carnitine-facilitated route to produce nuclear-cytosolic acetyl-CoA, shedding light on the intricate regulation and compartmentalization of acetyl-CoA metabolism

Overexpression of the MYC oncoprotein is an initiating step in the formation of several cancers. MYC frequently recruits chromatin-modifying complexes to DNA to amplify the expression of cancer-promoting genes, including those regulating cell cycle, proliferation, and metabolism, yet the roles of specific modifiers in different cancer types are not well defined. Here, we show that GCN5 is an essential coactivator of cell-cycle gene expression driven by MYC overexpression and that deletion of Gcn5 delays or abrogates tumorigenesis in the Eμ-Myc mouse model of B-cell lymphoma. Our results demonstrate that Gcn5 loss impacts both expression and downstream functions of Myc. Significance: Our results provide important proof of principle for Gcn5 functions in formation and progression of Myc-driven cancers, suggesting that GCN5 may be a viable target for development of new cancer therapies.

Targeting epigenetic regulators, such as histone-modifying enzymes, provides novel strategies for cancer therapy. The GCN5 lysine acetyltransferase (KAT) functions together with MYC both during normal development and in oncogenesis. As transcription factors, MYC family members are difficult to target with small-molecule inhibitors, but the acetyltransferase domain and the bromodomain in GCN5 might provide alternative targets for disruption of MYC-driven functions. GCN5 is part of two distinct multiprotein histone-modifying complexes, SAGA and ATAC. This review summarizes key findings on the roles of SAGA and ATAC in embryo development and in cancer to better understand the functional relationships of these complexes with MYC family members, as well as their future potential as therapeutic targets.