Sonic Hedgehog Signaling Pathway Promotes INSM1 Transcription Factor in Neuroendocrine Lung Cancer

Neuroendocrine (NE) lung tumors account for 20% of total lung cancer cases and represent a subset of aggressive tumors with metastatic potential. High-risk NE lung cancer patients display disseminated disease, N-myc expression/amplification, and poorly differentiated tumors. In this study, we investigate the molecular mechanisms underlying a zinc-finger transcription factor, INSM1 in NE lung cancer. Our study revealed that INSM1 crosstalk with the Shh-PI3K/AKT-N-myc/Ascl1-MEK/ERK transcriptional network in NE lung cancer. The INSM1 expression pattern and functional data demonstrated that INSM1 is not only critical for NE differentiation, but also served as a NE tumor-specific marker in small cell lung carcinoma (SCLC). The Shh signaling pathway activates INSM1 expression through N-myc and Ascl1 in aggressive SCLC. The E2-box in the INSM1 promoter is the direct target recognized by N-myc and Ascl1 transcription factors. N-myc or Ascl1 activates endogenous INSM1 expression in lung cancer cells. INSM1 functions as a key player in NE lung cancer via Shh signaling that crosstalk with PI3K/AKT and MEK/ERK pathway to enhance N-myc stability in NE lung cancer. We investigate the negative effects of Shh inhibitor and knockdown of INSM1 in NE lung cancer cells. The combination of different Shh signaling pathway inhibitors targeting INSM1 and N-myc inhibits lung cancer cell growth and could be used as a new treatment option for SCLC.