Forwards and Backwards
How a Gene Regulates Itself and its Anti-Sense Transcript

MYCN in cancer - has a coding overlapping gene

Gene amplification is a major mechanism for proto-oncogenes to result in overexpression. In almost a quarter of neuroblastomas, MYCN, was one of the first genes to show this pattern in cancer. The gene encodes a transcription factor, whose abnormal expression has been linked to poor prognosis and various types of high-risk cancers. For an excellent in-depth review of regulation and possible therapeutic targets, see Lui et al 2020.

While MYCN was being studied, researchers noticed that there was another gene that begins from intron 1 of MYCN, transcribed in the other direction. This makes it a cis (same strand) anti-sense (opposite direction) transcript, hence it was (unsurprisingly) called “NCYM”. The genes overlap and face opposite directions. When it was described in 1990, it was thought to be non-coding. It was not until much later, when the team of Yusuke Suenaga and Akira Nakagawara and their colleagues published an exposé to show that the NCYM gene is not only coding but also promotes tumor progression (Suenaga et al. 2014). The impact of their efforts is also summarized nicely in Suenaga et al. 2020, with particularly detailed regulatory pathways.

Source Suenaga et al. 2014

Historical aside: The name for the antisense gene is now officially called MYCN opposite strand → MYCNOS, but the historical NCYM name is still sometimes used.

MYCNOS drives up the expression of MYCN, and vice versa

MYCN upregulates itself: MYCN increases transcription by binding to an “E-box” in its intron 1. That also upregulates MYCNOS, which shares that intron.

MYCNOS inhibits MYCN ‘s negative regulator, GSK3β: directly and indirectly, MYCNOS blocks the kinase, GSK3β, that would typically phosphorylate MYCN to trigger degradation. In doing so, MYCNOS stabilizes MYCN.

Understanding the interplay between these genes and how they affect each other is critical to the treatment of the diseases they cause. In this case, for example, various treatments are applied to varying degrees of success to downregulate this pathway as it becomes overactive.

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