Recent advances in genetic analysis have led to further subtyping of small cell lung carcinoma (SCLC). The major subtypes of SCLC are the ASCL1-predominant (SCLC-A), NEUROD1-predominant (SCLC-N), and POU2F3 (SCLC-P) subtypes. SCLC-A and SCLC-N tumors express chromogranin A (CHGA) and synaptophysin (SYP), but SCLC-P tumors do not. Large cell neuroendocrine carcinoma (LCNEC), another type of neuroendocrine carcinoma (NEC), also frequently expresses CHGA and SYP. Since CHGA and SYP expression is controlled by a transrepressor, RE1-silencing transcription factor (REST), the mechanisms underlying REST suppression in NEC were investigated, with a focus on microRNAs and epigenetics, to determine the causes of the differences in the expression of CHGA and SYP between SCLC-A/N and SCLC-P cells. The results that miR-375-3p, which was induced by ASCL1 and NEUROD1, repressed REST expression by binding to the 3'-untranslated region of REST mRNA. Bisulfite sequencing and experiments using a DNA methyltransferase inhibitor, a histone deacetylase inhibitor, and chromatin immunoprecipitation-based quantitative polymerase chain reaction revealed that promoter/enhancer hypermethylation and histone deacetylation causes REST gene inactivation in SCLC-A/N. These phenomena were also observed in a large cell neuroendocrine carcinoma cell line that expressed high levels of ASCL1 and NEUROD1. Taken together, these findings suggest that NEC has dual repressive effects on REST expression, resulting in strict regulation of the expression of CHGA, SYP, and other REST-controlled neuronal/neuroendocrine-specific genes.
Konno et al. (Mon,) studied this question.