MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.

The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.

HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway.

HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) is a conserved long non-coding RNA (lncRNA) involved in myeloid and neural differentiation that is deregulated in acute myeloid leukemia and other cancers. Previous studies focused on the nuclear unspliced HOTAIRM1 transcript, however cytoplasmic splice variants exist whose roles have remained unknown. Here, we report novel functions of HOTAIRM1 in the kidney. HOTAIRM1 transcripts are induced during renal lineage differentiation of embryonic stem cells and required for expression of specific renal differentiation genes. We show that the major HOTAIRM1 transcript in differentiated cells is the spliced cytoplasmic HM1-3 isoform and that HM1-3 is downregulated in >90% of clear cell renal cell carcinomas (ccRCCs). Knockdown of HM1-3 in renal cells deregulates hypoxia-responsive and angiogenic genes, including ANGPTL4. Furthermore, HOTAIRM1 transcripts are downregulated by hypoxia-mimetic stress and knockdown of the cytoplasmic HM1-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1α (HIF1α) protein, a key activator of ANGPTL4. Our results demonstrate the pervasive downregulation of the specific HOTAIRM1 cytoplasmic isoform HM1-3 in ccRCC and suggest possible roles of HOTAIRM1 in kidney differentiation and suppression of HIF1-dependent angiogenic pathways.