NFS1 activity is essential for maintenance of iron–sulfur cluster biosynthesis in response to oxidative stress.

  • Major finding: NFS1 activity is essential for maintenance of iron–sulfur cluster biosynthesis in response to oxidative stress.

  • Concept:NFS1 is amplified in a subset of lung adenocarcinomas, and its loss suppresses lung tumor growth.

  • Impact: Inhibition of iron–sulfur cluster biosynthesis may sensitize tumor cells to oxidative stress.

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Oxygen levels alter the activity of oxygen-consuming enzymes, and this can lead to the observation of different dependencies in vitro (at 21% atmospheric oxygen levels) and in vivo (at tissue level oxygen ∼3%). To identify genes whose essentiality changes dependent on oxygen abundance, Alvarez, Sviderskiy, and colleagues performed RNAi-based loss-of-function screens and discovered that the cysteine desulfurase NFS1 is required in the lung in vivo and at 21% oxygen in vitro, but not at the lower oxygen levels representative of most normal tissues. NFS1 obtains sulfur from cysteine to biosynthesize iron–sulfur clusters, required cofactors in a number of human enzymes. Because oxygen degrades these cell essential cofactors, tumors in high-oxygen environments such as the lung required robust activity of NFS1 to meet iron–sulfur cluster metabolic demand. NFS1 depletion did not affect the growth of mammary or subcutaneous tumors, which grow in a hypoxic environment, but did suppress the growth of metastatic and primary lung tumors, which occur in a high-oxygen environment. Consistent with these findings, NFS1 was found to be amplified or overexpressed in in a subset of lung adenocarcinomas, and in a mouse model of lung cancer, NFS1 depletion prevented the growth of primary lung tumors. Mechanistically, NFS1 depletion limited iron–sulfur cluster availability as demonstrated by reduced oxygen consumption in cells cultured in 21% oxygen, but not 3%. Moreover, NFS1 depletion diminished aconitase activity, resulting in activation of the iron starvation response. NFS1 depletion sensitized cells to inhibition of glutathione biosynthesis, which increased ROS to result in tumor cell death by ferroptosis. Collectively, these findings suggest that lung adenocarcinomas select for high expression of NFS1 to protect against oxidative damage in the high-oxygen environment of the lung. Further, inhibition of iron–sulfur cluster biosynthesis may sensitize tumor cells to oxidative stress and promote ferroptosis.

Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 2017;551:639–43.

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