Human antigen R (HuR) SUMOylation controls senescence response in liver cancer

The clinical management of liver cancer is challenged by the reduced availability of drugs targeting key signaling pathways and their modest benefits to patients. Senescence induction may represent a strategy for cancer treatment, especially as a combination therapy. The posttranslational modification (PTM) of proteins critically influences many biological processes, including gene expression, cell proliferation, differentiation and apoptosis, tumor progression, and drug resistance. Herein, we newly discovered that the RNA-binding protein (RBP) Human antigen R (HuR), a hub in liver cancer, is SUMOylated in the tumor sections of patients with hepatocellular carcinoma (HCC) in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum (ER). Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs (RRMs) that modulates HuR binding affinity to its target mRNAs further modifying the transcriptomic profile towards hepatic tumor progression. Overall design: Profiling of RNAs interaction with SUMOylated and non-SUMOylated HuR by performing a V5-tagged HuR immunoprecipitation followed by the isolation and sequencing of the bound RNAs (RIP-Seq) in the human hepatoma HuH-7 cell line stably overexpressing WT HuR or expressing HuR(K120/182R) SUMOylation mutant.