LncRNA H19 Suppresses Osteosarcomagenesis by Regulating snoRNAs and DNA Repair Protein Complexes

An Xu; Mo-Fan Huang; Dandan Zhu; Julian A Gingold; Danielle A Bazer; Betty Chang; Donghui Wang; Chien-Chen Lai; Ihor R Lemischka; Ruiying Zhao; Dung-Fang Lee

doi:10.3389/fgene.2020.611823

LncRNA H19 Suppresses Osteosarcomagenesis by Regulating snoRNAs and DNA Repair Protein Complexes

Front Genet. 2021 Jan 15:11:611823. doi: 10.3389/fgene.2020.611823. eCollection 2020.

Authors

An Xu¹, Mo-Fan Huang¹, Dandan Zhu¹, Julian A Gingold², Danielle A Bazer³, Betty Chang^{4

5

6}, Donghui Wang¹, Chien-Chen Lai^{7

8}, Ihor R Lemischka^{4

5

6}, Ruiying Zhao¹, Dung-Fang Lee^{1

9

10

11}

Affiliations

¹ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
² Department of Obstetrics and Gynecology and Women's Health, Einstein/Montefiore Medical Center, Bronx, NY, United States.
³ Department of Neurology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United States.
⁴ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
⁵ The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
⁶ The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
⁷ Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.
⁸ Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.
⁹ The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States.
¹⁰ Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, United States.
¹¹ Center for Precision Health, School of Biomedical Informatics and School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States.

Abstract

Osteosarcoma is one of the most frequent common primary malignant tumors in childhood and adolescence. Long non-coding RNAs (lncRNAs) have been reported to regulate the initiation and progression of tumors. However, the exact molecular mechanisms involving lncRNA in osteosarcomagenesis remain largely unknown. Li-Fraumeni syndrome (LFS) is a familial cancer syndrome caused by germline p53 mutation. We investigated the tumor suppressor function of lncRNA H19 in LFS-associated osteosarcoma. Analyzing H19-induced transcriptome alterations in LFS induced pluripotent stem cell (iPSC)-derived osteoblasts, we unexpectedly discovered a large group of snoRNAs whose expression was significantly affected by H19. We identified SNORA7A among the H19-suppressed snoRNAs. SNORA7A restoration impairs H19-mediated osteogenesis and tumor suppression, indicating an oncogenic role of SNORA7A. TCGA analysis indicated that SNORA7A expression is associated with activation of oncogenic signaling and poor survival in cancer patients. Using an optimized streptavidin-binding RNA aptamer designed from H19 lncRNA, we revealed that H19-tethered protein complexes include proteins critical for DNA damage response and repair, confirming H19's tumor suppressor role. In summary, our findings demonstrate a critical role of H19-modulated SNORA7A expression in LFS-associated osteosarcomas.

Keywords: H19 lncRNA; Li-Fraumeni syndrome; iPSCs; osteosarcoma; p53; snoRNA.