De novo evolved gene product NCYM in the pathogenesis and clinical outcome of human neuroblastomas and other cancers

NCYM is an antisense transcript of MYCN oncogene and promotes tumor progression. NCYM encodes a de novo protein whose open reading frame evolved from noncoding genomic regions in the ancestor of Homininae. Because of its topology, NCYM is always co-amplified with MYCN oncogene, and the mutual regulations between NCYM and MYCN maintain their expressions at high levels in MYCN-amplified tumors. NCYM stabilizes MYCN by inhibiting GSK3β, whereas MYCN stimulates transcription of both NCYM and MYCN. NCYM mRNA and its noncoding transcript variants MYCNOS have been shown to stimulate MYCN expression via direct binding to MYCN promoter, indicating that both coding and noncoding transcripts of NCYM induce MYCN expression. In contrast to the noncoding functions of NCYM, NCYM protein also promotes calpain-mediated cleavage of c-MYC. The cleaved product called Myc-nick inhibits cell death and promotes cancer cell migration. Furthermore, NCYM-mediated inhibition of GSK3β results in the stabilization of β-catenin, which promotes aggressiveness of bladder cancers. These MYCN-independent functions of NCYM showed their clinical significance in MYCN-non-amplified tumors, including adult tumors. This year is the 30th anniversary of the identification of NCYM/MYCNOS gene. On this special occasion, we summarize the current understanding of molecular functions and the clinical significance of NCYM and discuss future directions to achieve therapeutic strategies targeting NCYM.