ZKSCAN3 represses a network of genes required for autophagy and lysosome biogenesis.

  • Major finding: ZKSCAN3 represses a network of genes required for autophagy and lysosome biogenesis.

  • Mechanism: Starvation induces shuttling of ZKSCAN3 to the cytoplasm and derepression of ZKSCAN3 targets.

  • Impact: A starvation-induced master switch controls an autophagy and lysosomal gene program.

Autophagy is a catabolic process in which cellular components are lysosomally degraded to maintain homeostasis under stress conditions. Defects in autophagy underlie many human diseases, including cancer, but how autophagy is regulated remains poorly understood. Chauhan and colleagues sought to characterize the cellular function of zinc finger with KRAB and SCAN domains 3 (ZKSCAN3), a zinc finger transcription factor previously shown to drive cancer cell proliferation, and found that ZKSCAN3 depletion inhibited cell growth by inducing senescence. ZKSCAN3 loss also led to a marked increase in autophagy and lysosome biogenesis that was required for senescence and growth inhibition. Consistent with these findings, pathway analysis of genes differentially expressed following ZKSCAN3 knockdown showed that autophagy was among the most highly upregulated cellular functions, suggesting that ZKSCAN3 regulates genes required for autophagy. Indeed, over 60 genes involved in different steps of autophagy as well as lysosome biogenesis and function were upregulated following ZKSCAN3 loss, and chromatin immunoprecipitation showed that some of these genes were direct ZKSCAN3 targets. To determine how ZKSCAN3 is endogenously suppressed under stress conditions that induce autophagy, the effects of nutrient depletion, hypoxia, and endoplasmic reticulum stress on ZKSCAN3 were evaluated. Starvation specifically led to increased ZKSCAN3 cytoplasmic accumulation in association with reduced ZKSCAN3 occupancy at target genes, indicating that altered ZKSCAN3 cellular localization in response to nutrient depletion promotes derepression of an autophagy transcriptional program. Together, these findings implicate ZKSCAN3 as a nutrient-responsive master regulator that simultaneously suppresses a large group of genes required for autophagy and lysosome biogenesis and as a key network node that could potentially be modulated for therapeutic benefit.

Chauhan S, Goodwin JG, Chauhan S, Manyam G, Wang J, Kamat AM, et al. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol Cell 2013 Feb 21 [Epub ahead of print].