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.