Enhanced autophagy and NFE2L2/NRF2 pathway activation in SPOP mutation-driven prostate cancer.

SQSTM1/p62 is a selective macroautophagy/autophagy receptor that drives ubiquitinated cargos toward the lysosome for degradation, and also a stress-induced scaffold protein that helps cells to cope with oxidative stress through sequestrating KEAP1 and subsequent activation of the NFE2L2/NRF2 antioxidant pathway. Accumulating evidence implicates SQSTM1 dysregulation in the induction of multiple oncogenic transformations in vivo. SPOP (speckle type BTB/POZ protein), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer (Pca), but the molecular mechanisms underlying how SPOP mutations contribute to PCa tumorigenesis are still largely unknown. In a recent study, we describe a new role for SPOP as a negative regulator of autophagy and NFE2L2 pathway activation. SPOP binds and induces the non-degradative ubiquitination of SQSTM1 at Lys420. This post-translational modification decreases SQSTM1 body formation, liquid phase condensation, dimerization, and ubiquitin-binding capacity, thereby suppressing SQSTM1-dependent autophagy, KEAP1 sequestration, and NFE2L2 activation. Notably, PCa-associated SPOP mutants lose the capacity to ubiquitinate SQSTM1 and instead enhance autophagy and the antioxidant response in a dominant-negative manner. Thus, our findings indicate the critical roles of autophagy and NFE2L2 pathway activation in PCa tumorigenesis by oncogenic SPOP mutations.