Autophagy Suppresses Tumorigenesis through Elimination of p62

Abstract

SUMMARY Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulate p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting 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-κB 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.

Mitophagy in hematopoietic stem cells

“…152,153 For example, by preventing the accumulation of damaged/dysfunctional organelles and protein aggregates, autophagy may suppress the formation of tumors (and function as a tumor suppressor); [154][155][156][157] by contrast, autophagy may enable tumor cell survival under adverse intracellular (i.e., from oncogenes) or extracellular (i.e., tumor microenvironment or in response to chemotherapy) conditions. 158,159 A similar picture may emerge for mitophagy as it becomes possible to separate autophagy and mitophagy by using genetic and/or pharmacological tools.…”

Neural-specific Deletion of FIP200 Leads to Cerebellar Degeneration Caused by Increased Neuronal Death and Axon Degeneration

“…These results provide further support that defective autophagy upon deletion of FIP200 is responsible for the accumulation of ubiquitinated protein aggregates. They also suggest that deletion of FIP200 resulted in accumulation of damaged mitochondria in neurons, which could be due to deficiency of autophagy in these cells (35).…”

YY1-MIR372-SQSTM1 regulatory axis in autophagy

“…Since SQSTM1 is degraded together with its cargo like misfolded proteins in autolysosomes, autophagy is supposed to be the main mechanism of SQSTM1 turnover and upregulation of SQSTM1 in tumor cells is the result of defective autophagy. 18,19 However, autophagy is not always defective in human cancers and the tumors developed in these genetically modified mice are benign but do not progress into carcinoma or metastatic lesions, indicating the presence of other mechanisms responsible for cancer-specific SQSTM1 upregulation. 19 Herein we present such a mechanism since inhibition of autophagy failed to rescue YY1-knockdown-induced SQSTM1 downregulation.…”

“…16 Since the discovery of BECN1, other studies have also shown that autophagy-deficient cells are more tumorigenic than their autophagy-competent counterparts. 17,18 In addition, mice harboring deletions in autophagy-related genes are more prone to tumorigenesis. 17,19 These data lead to the hypothesis that autophagy has tumor-suppressive functions.…”

“…[24][25][26] In addition, accumulation of SQSTM1 promotes tumorigenesis while inhibition of autophagy prevents tumor growth in nude mice. 18,27 Thus, the exact role of autophagy in human carcinogenesis is still a matter of debate. In addition, it remains largely unknown how autophagy is activated under different conditions and how autophagy modulators such as SQSTM1 are dysregulated in human cancers.…”