Integrins plays critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription, which upregulation is involved in
cancer stemness and
metastasis. However, the molecular mechanisms underlying how
integrins are upregulated in cancer stem cells (CSCs) remain as a biomedical mystery. Herein, we show that the death from
cancer signature gene USP22 is essential to maintain the stemness of
breast cancer cells through promoting the transcription of a group of
integrin family members in particular
integrin β1 (ITGB1). Both genetic and pharmacological USP22 inhibition largely impaired
breast cancer stem cell self-renewal and prevented their
metastasis.
Integrin β1 reconstitution partially rescued USP22-null
breast cancer stemness and their
metastasis. At the molecular level, USP22 functions as a bona fide
deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a
transcription factor for tumoral ITGB1 gene transcription. Importantly unbiased analysis of the TCGA database revealed a strong positive correlation between the death from
cancer signature gene
ubiquitin-specific peptidase 22 (USP22) and ITGB1, both of which are critical for
cancer stemness, in more than 90% of human
cancer types, implying that USP22 functions as a key factor to maintain stemness for a broad spectrum of human
cancer types possibly through regulating ITGB1. To support this notion, immunohistochemistry staining detected a positive correlation among USP22, FoxM1 and
integrin β1 in human breast
cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis critical for
cancer stemness and offers a potential target for antitumor
therapy.