Autophagy Enhanced by RASSF1A Suppresses Diethylnitrosamine (DEN)-Induced Hepatocarcinogenesis
Abstract
Hepatocellular carcinoma (HCC) is the most common type of human liver cancer and it is now the second leading cause of cancer death worldwide. In the United States, its incidence has tripled since 1980 and the death rates are increasing. RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor and frequently inactivated in HCC by promoter hypermethylation. However, the exact role and detailed mechanism of RASSF1A in the development of HCC has not been investigated.
Autophagy is a catabolic pathway to degrade dysfunctional organelles and misfolded or aggregated proteins. Autophagy defects enhance oxidative stresses which trigger DNA damage and genome instability to promote tumorigenesis. The interaction of RASSF1A with microtubule-associated autophagy activator MAP1S triggered us to examine whether RASSF1A itself activates autophagy to suppress HCC through MAP1S. We show here first time that RASSF1A is essential to maintain autophagy activity and RASSF1A depletion causes decreased autophagy flux both in vitro and in vivo. RASSF1A-deletion-caused autophagy defects lead to an acceleration of diethylnitrosamine (DEN)-induced HCC and a 31% reduction in mouse survivals.
RASSF1A activates autophagy by enhancing both autophagy initiation and maturation. RASSF1A does not impact MAP1S-Bcl-2-p27 non-canonical autophagy initiation pathway but acts through the Hippo pathway-regulatory protein Mst1 to promote autophagy initiation through PI3K-Akt-mTOR pathway, a major pathway suppressing autophagy initiation. Acetylated microtubules are required for the trafficking of autophagosomes to fuse with lysosomes. RASSF1A enhances microtubular acetylation and recruits LC3-II-associated autophagosomes onto RASSF1A-stabilized acetylated microtubules through MAP1S to promote autophagy maturation.
In sum, in addition to identify RASSF1A as a novel regulator of autophagy, we show here first time that the epigenetic inactivation of RASSF1A actually promotes HCC and shortens survivals by suppressing autophagy initiation and maturation, which may provide a novel paradigm of the prevention and therapy of HCC.
Citation
Li, Wenjiao (2017). Autophagy Enhanced by RASSF1A Suppresses Diethylnitrosamine (DEN)-Induced Hepatocarcinogenesis. Doctoral dissertation, Texas A & M University. Available electronically from https : / /hdl .handle .net /1969 .1 /173170.