Anti-SQSTM1 monoclonal antibody, clone 6G3 [Alexa Fluor® 647]

p62 is associated with 2 major cellular defense mechanisms against metabolic and oxidative stress, autophagy and the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor-E2-related factor 2 (NRF2) system. Recent studies indicate that the p62-KEAP1-NRF2 pathway promotes tumorigenesis and tumor growth mediated by NRF2-dependent antioxidative response. However, whether p62 is involved in bladder cancer (BCa) development remains unknown. Here, we found that p62 is overexpressed in BCa tissue and several BCa cell lines. The knockdown of p62 inhibits BCa cell growth both in vitro and in vivo, with increased intracellular reactive oxygen species level. Mechanically, p62 activates NRF2 signaling by sequestrating KEAP1, which leads to the upregulation of antioxidant genes (Gclc, Gstm5, and Gpx2), thus protecting BCa cells from oxidative stress. Our findings indicate that p62 might be involved in the development of BCa and serve as a potential therapeutic target.

Currently, most antioxidants do not show any favorable clinical outcomes in reducing myocardial ischemia-reperfusion (I/R) injury, suggesting an urgent need for exploring a new regulator of redox homeostasis in I/R hearts. Here, using heart-specific transgenic (TG) and knockdown (KD) mouse models, tumor susceptibility gene 101 (Tsg101) is defined as a novel cardiac-protector against I/R-triggered oxidative stress. RNA sequencing and bioinformatics data surprisingly reveal that most upregulated genes in Tsg101-TG hearts are transcribed by Nrf2. Accordingly, pharmacological inhibition of Nrf2 offsets Tsg101-elicited cardio-protection. Mechanistically, Tsg101 interacts with SQSTM1/p62 through its PRR domain, and promotes p62 aggregation, leading to recruitment of Keap1 for degradation by autophagosomes and release of Nrf2 to the nucleus. Furthermore, knockout of p62 abrogates Tsg101-induced cardio-protective effects during I/R. Hence, our findings uncover a previously unrecognized role of Tsg101 in the regulation of p62/Keap1/Nrf2 signaling cascades and provide a new strategy for the treatment of ischemic heart disease.