Autophagy enhanced by microtubule- and mitochondrion-associated MAP1S suppresses genome instability and hepatocarcinogenesis.
Dysfunctional autophagy is associated with tumorigenesis; however, the relationship between the two processes remains unclear. In the present study, we showed that MAP1S levels immediately become elevated in response to diethylnitrosamine-induced or genome instability-driven metabolic stress in a murine model of hepatocarcinoma. Upregulation of MAP1S enhanced autophagy to remove aggresomes and dysfunctional organelles that trigger DNA double-strand breaks and genome instability. The early accumulation of an unstable genome before signs of tumorigenesis indicated that genome instability caused tumorigenesis. After tumorigenesis, tumor development triggered the activation of autophagy to reduce genome instability in tumor foci. We, therefore, conclude that an increase in MAP1S levels triggers autophagy to suppress genome instability such that both the incidence of diethylnitrosamine-induced hepatocarcinogenesis and malignant progression are suppressed. Taken together, the data establish a link between MAP1S-enhanced autophagy and suppression of genomic instability and tumorigenesis.
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA.
Rui
R
Xie
Fen
F
Wang
Wallace L
WL
McKeehan
Leyuan
L
Liu
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001343:Autophagy; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D005260:Female; D042822:Genomic Instability; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*
D000477:Alkylating Agents; C570460:MAP1S protein, mouse; D008869:Microtubule-Associated Proteins; D004052:Diethylnitrosamine