Autophagy regulates tumor growth and metastasis.
Lei QiangBaozhong ZhaoMei MingNing WangTong-Chuan HeSeungmin HwangAndrew ThorburnYu-Ying HePublished in: bioRxiv : the preprint server for biology (2023)
The role of autophagy in tumorigenesis and tumor metastasis remains poorly understood. Here we show that inhibition of autophagy stabilizes the transcription factor Twist1 through Sequestosome-1 (SQSTM1, also known as p62) and thus increases cell proliferation, migration, and epithelial-mesenchymal transition (EMT) in tumor development and metastasis. Inhibition of autophagy or p62 overexpression blocks Twist1 protein degradation in the proteasomes, while p62 inhibition enhances it. SQSTM1/p62 interacts with Twist1 via the UBA domain of p62, in a Twist1-ubiquitination-dependent manner. Lysine 175 in Twist1 is critical for Twist1 ubiquitination, degradation, and SQSTM1/p62 interaction. For squamous skin cancer and melanoma cells that express Twist1, SQSTM1/p62 increases tumor growth and metastasis in mice. Together, our results identified Twist1 as a key downstream protein for autophagy and suggest a critical role of the autophagy/p62/Twist1 axis in cancer development and metastasis.
Keyphrases
- epithelial mesenchymal transition
- signaling pathway
- cell death
- endoplasmic reticulum stress
- transforming growth factor
- cell proliferation
- oxidative stress
- pi k akt
- squamous cell carcinoma
- skin cancer
- cell cycle
- high grade
- small molecule
- adipose tissue
- metabolic syndrome
- protein protein
- insulin resistance
- skeletal muscle
- high fat diet induced