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LY6K-AS lncRNA is a lung adenocarcinoma prognostic biomarker and regulator of mitotic progression

Abstract

Recent advances in genomics unraveled several actionable mutational drivers in lung cancer, leading to promising therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. However, the tumors’ acquired resistance to the newly-developed as well as existing therapies restricts life quality improvements. Therefore, we investigated the noncoding portion of the human transcriptome in search of alternative actionable targets. We identified an antisense transcript, LY6K-AS, with elevated expression in lung adenocarcinoma (LUAD) patients, and its higher expression in LUAD patients predicts poor survival outcomes. LY6K-AS abrogation interfered with the mitotic progression of lung cancer cells resulting in unfaithful chromosomal segregation. LY6K-AS interacts with and stabilizes 14-3-3 proteins to regulate the transcription of kinetochore and mitotic checkpoint proteins. We also show that LY6K-AS regulates the levels of histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of kinetochore members. Cisplatin treatment and LY6K-AS silencing affect many common pathways enriched in cell cycle-related functions. LY6K-AS silencing affects the growth of xenografts derived from wildtype and cisplatin-resistant lung cancer cells. Collectively, these data indicate that LY6K-AS silencing is a promising therapeutic option for LUAD that inhibits oncogenic mitotic progression.

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Fig. 1: Identification of clinically-relevant antisense lncRNAs in LUAD.
Fig. 2: LY6K-AS KD perturbs proliferation and cell cycle progression of LUAD cell lines.
Fig. 3: LY6K-AS KD interferes with mitosis and chromosomal segregation.
Fig. 4: LY6K-AS interacts with YWHAG.
Fig. 5: LY6K-AS regulates YWHAG stability.
Fig. 6: LY6K-AS expression sensitizes chemotherapy-resistant cell lines.

Data availability

The data associated with this publication have been deposited in GEO: GSE164419.

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Acknowledgements

This work was supported by the grants from Knut and Alice Wallenberg Foundation [KAW2014.0057]; Swedish Foundation for Strategic Research [RB13-0204]; Swedish Cancer Research foundation [Cancerfonden: Kontrakt no. CAN2018/591]; Swedish Research Council [2017-02834]; Barncancerfonden [PR2018-0090]; Ingabritt Och Arne Lundbergs forskningsstiftelse and LUA/ ALF (to CK). The Proteomics Core Facility at Gothenburg University, performed the analysis for protein identification. We acknowledge the Centre for Cellular Imaging at the University of Gothenburg for assisting in microscopy.

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Conceptualization—CK and MMA; Methodology—MMA, STK, SM, MDM, SR, DJ, CD, KM, and LS; Investigations—MMA, STK, SM, MDM, SR, DJ, CD, KM, and LS; Writing—original drafts- MMA; Writing—review and editing- MMA and CK; Funding acquisition, CK; Supervision, CK.

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Correspondence to Chandrasekhar Kanduri.

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Ali, M.M., Di Marco, M., Mahale, S. et al. LY6K-AS lncRNA is a lung adenocarcinoma prognostic biomarker and regulator of mitotic progression. Oncogene 40, 2463–2478 (2021). https://doi.org/10.1038/s41388-021-01696-7

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