Abstract
Although several somatic single nucleotide variations in histone H3.3 have been investigated as cancer drivers, other types of aberration have not been well studied. Here, we demonstrate that overexpression of H3F3A, encoding H3.3, is associated with lung cancer progression and promotes lung cancer cell migration by activating metastasis-related genes. H3.3 globally activates gene expression through the occupation of intronic regions in lung cancer cells. Moreover, H3.3 binding regions show characteristics of regulatory DNA elements. We show that H3.3 is deposited at a specific intronic region of GPR87, where it modifies the chromatin status and directly activates GPR87 transcription. The expression levels of H3F3A and GPR87, either alone or in combination, are robust prognostic markers for early-stage lung cancer, and may indicate potential for the development of treatments involving GPR87 antagonists. In summary, our results demonstrate that intronic regulation by H3F3A may be a target for the development of novel therapeutic strategies.
Highlights
Several somatic single nucleotide variations in histone H3.3 have been investigated as cancer drivers, other types of aberration have not been well studied
A variety of point mutations and copy number variations (CNV) in H3.3 genes are found at a low frequency in lung cancer samples, and many well-characterized mutations such as Lys27Met are not recurrent in lung cancer according to publicly available lung cancer data sets from the Catalogue of Somatic Mutations in Cancer database
We suggest that H3F3A overexpression in lung cancer promotes cancer progression, and we subsequently focused on H3F3A and stage I lung cancer
Summary
Several somatic single nucleotide variations in histone H3.3 have been investigated as cancer drivers, other types of aberration have not been well studied. We demonstrate that overexpression of H3F3A, encoding H3.3, is associated with lung cancer progression and promotes lung cancer cell migration by activating metastasis-related genes. H3.3 globally activates gene expression through the occupation of intronic regions in lung cancer cells. The expression levels of H3F3A and GPR87, either alone or in combination, are robust prognostic markers for early-stage lung cancer, and may indicate potential for the development of treatments involving GPR87 antagonists. Histone variants act as transcriptional activators or repressors of cancer-related genes. H2A.Z, another histone variant, promotes cancer progression via transcriptional regulation in various cancer types[9,10]. Many researchers have reported the transcriptional regulation activity of H3.3 on promoter and intergenic enhancer regions, transcriptional regulation via the binding of H3.3 to the intronic regions of target genes has not been well studied
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