Cancer Cell International (Nov 2023)

Interplay between lncRNA RP11-367G18.1 variant 2 and YY1 plays a vital role in hypoxia-mediated gene expression and tumorigenesis

  • Pei-Hua Peng,
  • Ji-Lin Chen,
  • Heng-Hsiung Wu,
  • Wen-Hao Yang,
  • Li-Jie Lin,
  • Joseph Chieh-Yu Lai,
  • Jeng-Shou Chang,
  • Jia-Ling Syu,
  • Han-Tsang Wu,
  • Fei-Ting Hsu,
  • Wei-Chung Cheng,
  • Kai-Wen Hsu

DOI
https://doi.org/10.1186/s12935-023-03067-6
Journal volume & issue
Vol. 23, no. 1
pp. 1 – 13

Abstract

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Abstract Background The hypoxia-responsive long non-coding RNA, RP11-367G18.1, has recently been reported to induce histone 4 lysine 16 acetylation (H4K16Ac) through its variant 2; however, the underlying molecular mechanism remains poorly understood. Methods RNA pull-down assay and liquid chromatography-tandem mass spectrometry were performed to identify RP11-367G18.1 variant 2-binding partner. The molecular events were examined utilizing western blot analysis, real-time PCR, luciferase reporter assay, chromatin immunoprecipitation, and chromatin isolation by RNA purification assays. The migration, invasion, soft agar colony formation, and in vivo xenograft experiments were conducted to evaluate the impact of RP11-367G18.1 variant 2–YY1 complex on tumor progression. Results In this study, RNA sequencing data revealed that hypoxia and RP11-367G18.1 variant 2 co-regulated genes were enriched in tumor-related pathways. YY1 was identified as an RP11-367G18.1 variant 2-binding partner that activates the H4K16Ac mark. YY1 was upregulated under hypoxic conditions and served as a target gene for hypoxia-inducible factor-1α. RP11-367G18.1 variant 2 colocalized with YY1 and H4K16Ac in the nucleus under hypoxic conditions. Head and neck cancer tissues had higher levels of RP11-367G18.1 and YY1 which were associated with poor patient outcomes. RP11-367G18.1 variant 2–YY1 complex contributes to hypoxia-induced epithelial–mesenchymal transition, cell migration, invasion, and tumorigenicity. YY1 regulated hypoxia-induced genes dependent on RP11-367G18.1 variant 2. Conclusions RP11-367G18.1 variant 2–YY1 complex mediates the tumor-promoting effects of hypoxia, suggesting that this complex can be targeted as a novel therapeutic strategy for cancer treatment.

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