Autophagy suppresses tumorigenesis through elimination of p62. Cell

Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-pronesuggesting that autophagy isa tumor-suppres-sion mechanism. While tumor cells utilize autophagy to survivemetabolic stress, autophagy alsomitigates the resulting cellular damage that may limit tumori-genesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage result-ing from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis