Myc and Miz-1 control melanocyte senescence by regulating intracellular cystathionase levels

The development of malignant melanoma is a highly complex process which is still poorly understood despite extensive research. A majority of human melanomas are found to express a handful of oncogenic proteins, such as mutant RAS and BRAF. However, these oncogenes are also found in nevi, and it is now a well-accepted fact that their expression alone leads to senescence. This renders the understanding of senescence escape mechanisms an important criterion to understand tumor development. Here, we describe the ability of the transcription factor MYC to drive the evasion of reactive oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling. Conversely, MIZ1, the growth suppressing interaction partner of MYC, is involved in mediating melanocyte senescence. Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive oxygen species (ROS), DNA damage and senescence. We identified the cystathionase (CTH) gene product as mediator of the ROS-related MYC and MIZ1 effects. Blocking CTH enzymatic activity in MYC-overexpressing and Miz1 knockdown cells increased intracellular stress and senescence. Importantly, pharmacological inhibition of cystathionase in human melanoma cells also reconstituted senescence in many cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H2O2 resistance and soft agar growth. Thus, we identified cystathionase as new MYC target gene with an important function in MYC-mediated senescence evasion.

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