Class III/IV POU transcription factors expressed in small cell lung cancer cells are involved in proneural/neuroendocrine differentiation

One‐third of lung malignancies demonstrate a proneural/neuroendocrine phenotype or type of differentiation. However, it has not been clearly elucidated how proneural/neuroendocrine differentiation is controlled in lung cancers. We recently demonstrated that the POU3F2 gene plays a significant role in proneural/neuroendocrine differentiation of lung cancers. Because class III POU genes ( POU3F1 , POU3F2 , POU3F3 , and POU3F4 ) and class IV POU genes ( POU4F1 , POU4F2 , and POU4F3 ) share similar properties in neural development, we analyzed the association between class III / IV POU genes and a proneural/neuroendocrine phenotype in lung cancers using seven small cell lung cancer ( SCLC ) cell lines and twelve non‐ SCLC ( NSCLC ) cell lines. Class III / IV POU gene expression was generally restricted to SCLC cells. However, the forced expression of class III / IV POU genes in the NSCLC cell lines induced the expression of neuroendocrine‐specific markers (neural call adhesion molecule 1, synaptophysin, and chromogranin A) and proneural transcription factors (achaete‐scute homolog‐like 1, Neuro D 1, and thyroid transcription factor 1) in various degrees. Furthermore, each class III / IV POU gene induced other class III / IV POU genes, suggesting the mutual induction of class III / IV POU genes. These findings suggest that the expression of class III / IV POU genes is important for the proneural/neuroendocrine differentiation of lung cancer cells.