RIP1–HAT1–SIRT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis and necroptosis has been attributed to RIP1/3 complexes. Experimental design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis and in vivo studies with different mice models. Results: Here, we show that RIP1 is highly expressed in cancer and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass Spectrometry identified 5 acetylations in the kinase and death domain of RIP1. The novel characterised pan-SirT inhibitor, MC2494, increases RIP1 acetylation at 2 additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death suggesting a role for acetylation of the RIP1 complex in cell death...