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LINC00162 confers sensitivity to 5-Aza-2′-deoxycytidine via modulation of an RNA splicing protein, HNRNPH1

Abstract

DNA demethylation therapy is now expanding from hematological tumors to solid tumors. To exploit its maximum efficacy, long-term treatment is needed, and stratification of sensitive patients is critically important. Here, we identified a long non-coding RNA, LINC00162, as highly and frequently expressed in gastric cancer cell lines sensitive to 5-aza-2′-deoxycytidine (5-aza-dC). Knockdown of LINC00162 decreased the sensitivity while its overexpression increased the sensitivity. In vivo experiments also showed that LINC00162 overexpression increased the sensitivity. LINC00162 enhanced cell cycle arrest and apoptosis induced by 5-aza-dC, but did not affect its DNA demethylation effect. Mechanistically, LINC00162 interacted with an RNA splicing protein, HNRNPH1, and decreased splicing of an anti-apoptotic splicing variant, BCL-XL. LINC00162 may have translational value to predict patients who will respond to 5-aza-dC.

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Acknowledgments

This study was supported by AMED under Grant Number JP18ck0106421 to Toshikazu Ushijima and JSPS KAKENHI under Grant Number JP18H02704 to Toshikazu Ushijima.

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T.U., L.Z. and N.H. designed the study; L.Z., N.H., Y.Y. and K.K. performed most of the experiments; A.M., K.K. and N.H. performed in vivo experiments; L.Z. and N.H. wrote the manuscript; T.U., N.H., Y.Y. and Y.S. revised the manuscript; and all authors read and approved the manuscript.

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Correspondence to Toshikazu Ushijima.

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Zong, L., Hattori, N., Yasukawa, Y. et al. LINC00162 confers sensitivity to 5-Aza-2′-deoxycytidine via modulation of an RNA splicing protein, HNRNPH1. Oncogene 38, 5281–5293 (2019). https://doi.org/10.1038/s41388-019-0792-8

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