Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma

Jimyung Seo, HyunSeok Kim, Kyoung Il Min, Changgon Kim, Yongsoo Kwon, Zhenlong Zheng, Yusung Kim, Hyung-Soon Park, Young Seok Ju, Mi Ryung Roh (), Kee Yang Chung () and Joon Kim ()
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Jimyung Seo: Korea Advanced Institute of Science and Technology (KAIST)
HyunSeok Kim: Korea Advanced Institute of Science and Technology (KAIST)
Kyoung Il Min: Korea Advanced Institute of Science and Technology (KAIST)
Changgon Kim: Korea Advanced Institute of Science and Technology (KAIST)
Yongsoo Kwon: Korea Advanced Institute of Science and Technology (KAIST)
Zhenlong Zheng: Cutaneous Biology Research Institute, Yonsei University College of Medicine
Yusung Kim: Korea Advanced Institute of Science and Technology (KAIST)
Hyung-Soon Park: Korea Advanced Institute of Science and Technology (KAIST)
Young Seok Ju: Korea Advanced Institute of Science and Technology (KAIST)
Mi Ryung Roh: Cutaneous Biology Research Institute, Yonsei University College of Medicine
Kee Yang Chung: Cutaneous Biology Research Institute, Yonsei University College of Medicine
Joon Kim: Korea Advanced Institute of Science and Technology (KAIST)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Acral melanoma commonly occurs in areas that are not exposed to much sunlight, such as the sole of the foot. Little is known about risk factors and mutational processes of plantar acral melanoma. Nuclear envelope rupture during interphase contributes to genome instability in cancer. Here, we show that the nuclear and micronuclear membranes of melanoma cells are frequently ruptured by macroscopic mechanical stress on the plantar surface due to weight-bearing activities. The marginal region of plantar melanoma nodules exhibits increased nuclear morphological abnormalities and collagen accumulations, and is more susceptible to mechanical stress than the tumor center. An increase in DNA damage coincides with nuclear membrane rupture in the tumor margin. Nuclear envelope integrity is compromised by the mechanosensitive transcriptional cofactor YAP activated in the tumor margin. Our results suggest a mutagenesis mechanism in melanoma and explain why plantar acral melanoma is frequent at higher mechanical stress points.

Date: 2022
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DOI: 10.1038/s41467-022-29925-x

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