An achaete-scute homologue essential for neuroendocrine differentiation in the lung

Authors:
  • RLR. Ilona Linnoila
    R. Ilona Linnoila
  • HVHelgi J. K. van de Velde
    Helgi J. K. van de Velde
  • HCHerbert Chen
    Herbert Chen
  • BNBarry D. Nelkin
    Barry D. Nelkin
  • MMMack Mabry
    Mack Mabry
  • SBStephen B. Baylin
    Stephen B. Baylin
  • DBDouglas W. Ball
    Douglas W. Ball
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Abstract
In Drosophila and in vertebrates, the achaete-scute family of basic helix-loop-helix transcription factors plays a critical developmental role in neuronal commitment and differentiation. Relatively little is known, however, about the transcriptional control of neural features in cells outside a neuronal context. A minority of normal bronchial epithelial cells and many lung cancers, especially small-cell lung cancer, exhibit a neuroendocrine phenotype that may reflect a common precursor cell population. We show here that human achaete-scute homologue-1 (hASH1) is selectively expressed in normal fetal pulmonary neuroendocrine cells, as well as in the diverse range of lung cancers with neuroendocrine features. Strikingly, newborn mice bearing a disruption of the ASH1 gene have no detectable pulmonary neuroendocrine cells. Depletion of this transcription factor from lung cancer cells by antisense oligonucleotides results in a significant decrease in the expression of neuroendrocrine markers. Thus, a homologue of Drosophila neural fate determination genes seems to be necessary for progression of lung epithelial cells through a neuroendocrine differentiation pathway that is a feature of small-cell lung cancer, the most lethal form of human lung cancer.

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