Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis

Yang Zhao, Jingyuan Ning, Hongqi Teng, Yalan Deng, Marisela Sheldon, Lei Shi, Consuelo Martinez, Jie Zhang, Annie Tian, Yutong Sun, Shinichi Nakagawa, Fan Yao, Hai Wang and Li Ma ()
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Yang Zhao: The University of Texas MD Anderson Cancer Center
Jingyuan Ning: Chinese Academy of Medical Sciences
Hongqi Teng: The University of Texas MD Anderson Cancer Center
Yalan Deng: The University of Texas MD Anderson Cancer Center
Marisela Sheldon: The University of Texas MD Anderson Cancer Center
Lei Shi: The University of Texas MD Anderson Cancer Center
Consuelo Martinez: The University of Texas MD Anderson Cancer Center
Jie Zhang: The University of Texas MD Anderson Cancer Center
Annie Tian: Rice University
Yutong Sun: The University of Texas MD Anderson Cancer Center
Shinichi Nakagawa: Hokkaido University
Fan Yao: The University of Texas MD Anderson Cancer Center
Hai Wang: Roswell Park Comprehensive Cancer Center
Li Ma: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract MALAT1, one of the few highly conserved nuclear long noncoding RNAs (lncRNAs), is abundantly expressed in normal tissues. Previously, targeted inactivation and genetic rescue experiments identified MALAT1 as a suppressor of breast cancer lung metastasis. On the other hand, Malat1-knockout mice are viable and develop normally. On a quest to discover the fundamental roles of MALAT1 in physiological and pathological processes, we find that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Remarkably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis of melanoma and mammary tumor cells, which can be rescued by genetic add-back of Malat1. Mechanistically, Malat1 binds to Tead3 protein, a macrophage-osteoclast–specific Tead family member, blocking Tead3 from binding and activating Nfatc1, a master regulator of osteoclastogenesis, which results in the inhibition of Nfatc1-mediated gene transcription and osteoclast differentiation. Notably, single-cell transcriptome analysis of clinical bone samples reveals that reduced MALAT1 expression in pre-osteoclasts and osteoclasts is associated with osteoporosis and metastatic bone lesions. Altogether, these findings identify Malat1 as a lncRNA that protects against osteoporosis and bone metastasis.

Date: 2024
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DOI: 10.1038/s41467-024-46602-3

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