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Abstract
Seong-Min Park1,*, Eun-Young Choi1,*, Mingyun Bae2, Sunshin Kim3, Jong Bae Park1,4, Heon Yoo1, Jung Kyoon Choi2, Youn-Jae Kim1, Seung-Hoon Lee1 & In-Hoo Kim4
1 Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea. 2 Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea. 3 Precision Medicine Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea. 4 Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea.
* These authors contributed equally to this work.
Correspondence and requests for materials should be addressed to Y.-J.K. or to S.-H.L..
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.
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