Steroid receptor coactivators (SRCs) are involved in the transcriptional regulation (co-activation) of nuclear receptors but can also act as oncogenes. These coactivators are usually considered as “undruggable” because of their large and flexible structures. We have found that an SRC-targeting agent SI-2, which selectively reduces protein concentrations of SRC1/2/3, inhibits cancer cell proliferation by restoring endogenous levels of the tumor suppressor C/EBPα along with lung specific transcription factor TTF-1 and NF-κB-p65. C/EBPα together with NF-κB-p65 and TTF1 are also known to increase fetal lung epithelial cell differentiation transcriptional program and alveolar type II cell identity. This suggests that steroid receptor coactivators Inhibitor (SI-2) may drive C/EBPα-mediated reprogramming to an alveolar type II cell fate in Non-Small Cell Lung Cancer (NSCLC).
