View ORCID ProfileJi Hoon Lee1,†, View ORCID ProfileJuyeong Hong1,†, View ORCID ProfileZhao Zhang1,†, View ORCID ProfileBárbara de la Peña Avalos2,3, View ORCID ProfileCecilia J. Proietti4, View ORCID ProfileAgustina Roldán Deamicis4, View ORCID ProfilePablo Guzmán G.5, Hung-Ming Lam6, Jose Garcia6, Martine P. Roudier6, View ORCID ProfileAnthony E. Sisk7, View ORCID ProfileRichard De La Rosa1, View ORCID ProfileKevin Vu8, Mei Yang1, Yiji Liao1, View ORCID ProfileJessica Scheirer1, View ORCID ProfileDouglas Pechacek1, Pooja Yadav9,10, View ORCID ProfileManjeet K. Rao9,10, Siyuan Zheng10,11, View ORCID ProfileTeresa L. Johnson-Pais12, View ORCID ProfileRobin J. Leach3,9, View ORCID ProfilePatricia V. Elizalde4, View ORCID ProfileEloïse Dray2,3 and View ORCID ProfileKexin Xu1,*
Abstract
The role of RNA methylation on N6-adenosine (m6A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m6A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m6A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m6A-editing tools further prove that the methyl groups on HMBOX1 per se contribute to the generation of the altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase METTL3 is negatively correlated with the telomere length but favorably with fractions of the altered cancer genome, whereas HMBOX1 mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying a particular epitranscriptomic program.
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Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to the understanding of its causes, and accelerate the translation of knowledge into novel therapies. Through discovery, development, and dissemination of new scientific knowledge, Greehey CCRI strives to have a national and global impact on childhood cancer. Our mission consists of three key areas — research, clinical, and education.
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