SMARCA6-LINC00559-ZBTB18 Axis Accelerates Cancer Progression Depending on LINC00559

The interplay between chromatin remodeling factors and lncRNAs is crucial for the regulation of gene expression and diseases including cancer, however, the precise role of lncRNAs in tumorigenesis still remains elusive. Here we demonstrated the role of a SMARC6-interacting long non-coding RNA (LINC00559) in NSCLC tumorigenicity. Gain- and loss-of-function studies show that LINC00559 promotes cancer cell growth, colony formation and cell-cycle progression in vitro as well as in xenograft mice. Mechanistically, LINC00559 recruits SMARCA6 and ZBTB18 to regulate the transcription of CDKN2B in trans. The precise key RNA binding amino acid residues within SMARCA6 and ZBTB18 are identified through their interaction with LINC00559 depending on this lncRNA, respectively. Furthermore, truncated LINC00559 or treatment with FX1 (an inhibitor of BTB domain) inhibits the formation of the SMARCA6-LINC00559-ZBTB18 complex and represses lung cancer progression. Thus, our study highlights that lncRNA might dependently dock transcription factor and chromatin modifier to regulate gene expression in trans, and truncations of lncRNA function as dominant negative mutants, as well as FX1, thus holding novel potential in targeted therapy against cancer.