CKAP2L promotes non-small cell lung cancer progression through regulation of transcription elongation
La Montagna, Manuela
Baker, Alexander R
Leong, Hui Sun
AffiliationCRUK MI, University of Manchester.
MetadataShow full item record
AbstractChromosomal instability (CIN) is a driver of clonal diversification and intra-tumor heterogeneity, providing genetic diversity that contributes to tumor progression. It is estimated that ∼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.
CitationMonteverde T, Sahoo S, La Montagna M, Magee P, Shi L, Lee D, et al. CKAP2L promotes non-small cell lung cancer progression through regulation of transcription elongation. Cancer Res. 2021.
- CKAP2L Knockdown Exerts Antitumor Effects by Increasing miR-4496 in Glioblastoma Cell Lines.
- Authors: Li YF, Tsai WC, Chou CH, Huang LC, Huang SM, Hueng DY, Tsai CK
- Issue date: 2020 Dec 27
- Up-regulation of CKAP2L expression promotes lung adenocarcinoma invasion and is associated with poor prognosis.
- Authors: Xiong G, Li L, Chen X, Song S, Zhao Y, Cai W, Peng J
- Issue date: 2019
- Oncogenic and prognostic role of CKAP2L in hepatocellular carcinoma.
- Authors: Wang P, He X
- Issue date: 2020
- A screen for selective killing of cells with chromosomal instability induced by a spindle checkpoint defect.
- Authors: Shaukat Z, Wong HW, Nicolson S, Saint RB, Gregory SL
- Issue date: 2012
- Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
- Authors: Hussain MS, Battaglia A, Szczepanski S, Kaygusuz E, Toliat MR, Sakakibara S, Altmüller J, Thiele H, Nürnberg G, Moosa S, Yigit G, Beleggia F, Tinschert S, Clayton-Smith J, Vasudevan P, Urquhart JE, Donnai D, Fryer A, Percin F, Brancati F, Dobbie A, Smigiel R, Gillessen-Kaesbach G, Wollnik B, Noegel AA, Newman WG, Nürnberg P
- Issue date: 2014 Nov 6