🇬🇧 The interplay of caspase-8 and p53 in malignant melanoma

Abstract

Mutations in p53 is a hallmark of tumor development leading to loss-of-function or gain-of-function. Consequently, cancer cells resist p53-dependent cell cycle checkpoints and intrinsic apoptosis. Intriguingly, the residual 50% of tumors can still progress with wildtype (wt)p53 indicating that these tumor cells have adapted alternative mechanisms suppressing wtp53 functions.
We have recently identified a non-canonical role of caspase-8 in the nucleus of MM that allows tumor cells with wildtype p53 (wtp53) activity to establish a de facto p53 protein loss, shifting cell fate from cell cycle arrest and apoptosis towards mitotic cell division at the G2/M checkpoint. In the nucleus, caspase-8
cleaves and inactivates the deubiquitinase USP28, preventing it from de-ubiquitinating and stabilizing wtp53. Integration of these different molecular
mechanisms may pave the way for the identification of new therapeutic targets or the reactivation of conventional approaches, like chemotherapy, to
provide improved and tailored treatment options.