CKAP2L Promotes Non-Small Cell Lung Cancer Progression through Regulation of Transcription Elongation.
Tiziana MonteverdeSudhakar SahooManuela La MontagnaPeter MageeLei ShiDave LeeRobert SellersAlexander R BakerHui Sun LeongAngelo Paolo Dei TosMichela GarofaloPublished in: Cancer research (2021)
Chromosomal instability (CIN) is a driver of clonal diversification and intratumor heterogeneity, providing genetic diversity that contributes to tumor progression. It is estimated that approximately 80% of solid cancers, including non-small cell lung cancer (NSCLC), exhibit features of CIN, which affects tumor growth and response to therapy. However, the molecular mechanisms connecting CIN to tumor progression are still poorly understood. Through an RNAi screen performed on genes involved in CIN and overexpressed in human lung adenocarcinoma samples, we identified the cytoskeleton-associated protein 2-like (CKAP2L) as a potential oncogene that promotes lung cancer proliferation and growth in vitro and in vivo. Mechanistically, CKAP2L directly interacted with RNA Pol II and regulated transcription elongation of key genes involved in spindle assembly checkpoint, chromosome segregation, cell cycle, and E2F signaling. Furthermore, depletion of CKAP2L increased the sensitivity of NSCLC cells to alvocidib, a pan-CDK inhibitor, leading to a significant reduction of cell proliferation and an increase in cell death. Altogether, these findings shed light on the molecular mechanisms through which CKAP2L, a protein involved in CIN, promotes cancer progression and suggest that its inhibition represents a novel therapeutic strategy in NSCLC. SIGNIFICANCE: These findings demonstrate the oncogenic function of CKAP2L through regulation of transcription elongation and suggest that targeting CKAP2L could enhance therapeutic response in patients with NSCLC.
Keyphrases
- cell cycle
- cell proliferation
- small cell lung cancer
- transcription factor
- advanced non small cell lung cancer
- cell death
- genetic diversity
- poor prognosis
- cell cycle arrest
- brain metastases
- induced apoptosis
- signaling pathway
- high throughput
- squamous cell carcinoma
- human health
- pi k akt
- dna methylation
- genome wide
- smoking cessation
- long non coding rna
- lymph node metastasis
- induced pluripotent stem cells