Lung adenocarcinoma (LUAD) is one of the important components of non-small-cell lung cancer (NSCLC) and leads to many deaths every year. During the initiation and progression of the LUAD, the Hh-GLI2 pathway plays critical roles. Several components of this pathway have been shown to be amplified or overexpressed in LUAD, providing this pathway as an attractive target for therapeutics. However, a gap in our understanding of the Hh-GLI2 pathway is the identity of transcriptional targets of GLI2 that drive LUAD tumorigenesis. Here, we show that the oncogene CRKL is a direct target of GLI2. GLI2 turns on CRKL transcription through binding its second intron. Furthermore, CRKL is an essential mediator for GLI2-driven proliferation and migration of LUAD cells. Depletion of CRKL blunts Hh-GLI2 pathway-mediated cell proliferation and invasion. Lastly, we find that CRKL knockout cells are more sensitive to EGFR-TKI and chemotherapeutics. Taken together, our work here identifies a specific target for Hh-related malignancies and provides CRKL as a promising therapeutic target for LUAD.
Keywords: CRKL; GLI2; Hh; LUAD.
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.