The emerging roles of α-tubulin N-acetyltransferase 1 (ATAT1) in autophagy induction and ferroptosis susceptibility in cancer cells

α-tubulin-N-acetyltransferase-1 (ATAT1) has recently been identified as the writer of α-tubulin acetylation on lysine-40 (K40). Tubulin acetylation has recently been implicated in the regulation of the autophagic pathway. However, the involvement of ATAT1 in this process remains to be elucidated. To fill this gap, we employed different cancer cell lines in which we transiently or stably silenced the ATAT1 enzyme. The results demonstrated that ATAT1 silencing increases the formation of LC3-positive autophagosomes and modulates the expression of several autophagic markers, under basal conditions and in response to starvation. Interestingly, ATAT1 silenced cells also produce a significantly higher amount of reactive oxygen species (ROS) and lipid peroxides, accompanied by alterations in mitochondrial dynamics, under both basal and stress conditions. Furthermore, stably silencing ATAT1 resulted in a reduction of ATP production, and a reduced oxygen consumption rate compared to the control cells. Mechanistically, ATAT1 silenced cells have alterations in the expression of several antioxidant genes, and in genes involved in glutathione metabolism and ferroptosis signaling pathway. In line with these findings, ATAT1 silencing sensitizes lung cancer cells to ferroptotic cell death. Taken together, these results reveal new roles for ATAT1 in autophagy regulation and in mitochondrial homeostasis, which are crucial for sustaining tumor cell growth and for defense against ferroptosis.