F-box protein FBXO41 suppresses breast cancer growth by inducing autophagic cell death through facilitating proteasomal degradation of oncogene SKP2.

F-box proteins form SCF (Cullin1, SKP1 and F-box-protein) ubiquitin ligase complexes to ubiquitinate cellular proteins. They play key role in several biological processes, including cell cycle progression, cellular signaling, stress response and cell death pathways. Therefore, deregulation of F-box proteins is closely associated with cancer progression. However, the role of most of the F-box proteins, including FBXO41, in cancer progression remains elusive. Here, we unravel the role of FBXO41 in cancer progression. We show that FBXO41 suppresses cancer cell proliferation and tumor growth by inducing autophagic cell death through an alternative pathway. Results revealed that FBXO41-mediated autophagic cell death induction is dependent on accumulation of cell cycle checkpoint protein p21. We found that FBXO41 increases the expression levels of p21 at the post-translational level by promoting the proteasomal degradation of SKP2, an oncogenic F-box protein. Mechanistically, FBXO41 along with p21 disrupts the inhibitory BCL2 (anti-apoptotic protein)-Beclin1 (autophagy initiating factor) complex of autophagy induction to release Beclin1, thereby inducing autophagy. Overall, the present study establishes a new FBXO41-SKP2-p21 axis for induction of autophagic cell death to prevent cancer growth, which could be explored to develop promising cancer therapeutics.