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Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells.

Molecular cell (2017-10-17)
Kai Liu, Jiyoung Lee, Ja Yeon Kim, Linya Wang, Yongjun Tian, Stephanie T Chan, Cecilia Cho, Keigo Machida, Dexi Chen, Jing-Hsiung James Ou
ABSTRACT

Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here, we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When mitophagy is enhanced, p53 co-localizes with mitochondria and is removed by a mitophagy-dependent manner. However, when mitophagy is inhibited, p53 is phosphorylated at serine-392 by PINK1, a kinase associated with mitophagy, on mitochondria and translocated into the nucleus, where it binds to the NANOG promoter to prevent OCT4 and SOX2 transcription factors from activating the expression of NANOG, a transcription factor critical for maintaining the stemness and the self-renewal ability of CSCs, resulting in the reduction of hepatic CSC populations. These results demonstrate that mitophagy controls the activities of p53 to maintain hepatic CSCs and provide an explanation as to why autophagy is required to promote hepatocarcinogenesis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Carbonyl cyanide 3-chlorophenylhydrazone, ≥97% (TLC), powder
Sigma-Aldrich
3-Methyladenine, autophagy inhibitor
Sigma-Aldrich
3-Hydroxy-1,2-dimethyl-4(1H)-pyridone, 98%
Sigma-Aldrich
Anti-LC3B antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-p53 (Ab-1) (Pantropic) Mouse mAb (PAb421), liquid, clone PAb421, Calbiochem®
Sigma-Aldrich
Anti-p53 (Ab-2) (Pantropic) Mouse mAb (PAb1801), liquid, clone PAb1801, Calbiochem®