Overexpressed PRR11-SKA2-miR301a/454 bidirectional transcription unit essentially and coordinately promotes PI3K-AKT pathway activation and lung cancer progression

Gene pairing is a highly conserved and special mode of eukaryotic gene organization, and critically implicated in development and diseases including cancer. We previously found that PRR11 and SKA2 constitute a classic head-to-head gene pair. Here, we further demonstrate that PRR11, SKA2, and its intronic miR301a and miR454 constitute a more exquisite bidirectional transcription unit that are overexpressed in various types of cancers. Functional studies using lung cancer as a model system reveal that co-overexpression of PRR11, SKA2, miR301a and miR454 together remarkably accelerates cell growth, cell cycle progression and cell motility in lung cancer cells, and promotes tumor growth in mouse models in vivo, whereas CRISPRi-mediated repression of the entire transcription unit inhibits these malignant phenotypes. Mechanistically, the four component genes do not display any additive or synergistic effect, but rather compensate for each other for robustly sustained activation of PI3K-AKT pathway, with PRR11 interacting with GRB2, and SKA2 with EGFR. Notably, miR301a and miR454 exert their oncogenic functions at least partially via repressing PTEN translation. Moreover, the transcription unit presents as a prominent prognostic meta-marker for lung cancer. Collectively, these findings demonstrate the essential and coordinated roles of PRR11-SKA2-miR301a/454 bidirectional transcription unit in lung cancer progression, highlighting its potential diagnostic and therapeutic values in cancers.