Highlights d Glucose regulates DOT1L protein stability through DOT1L O-GlcNAcylation d O-GlcNAcylation increases DOT1L stability and decreases its ubiquitination by UBE3C d DOT1L O-GlcNAcylation promotes MLL-fusion leukemia cell
Prevalent dysregulation of epigenetic modifications plays a pivotal role in cancer. Targeting epigenetic abnormality is a new strategy for cancer therapy. Understanding how conventional oncogenic factors cause epigenetic abnormality is of great basic and translational value. O-GlcNAcylation is a protein modification which affects physiology and pathophysiology. In mammals, O-GlcNAcylation is catalyzed by one single enzyme OGT and removed by one single enzyme OGA. O-GlcNAcylation is affected by the availability of the donor, UDP-GlcNAc, generated by the serial enzymatic reactions in the hexoamine biogenesis pathway (HBP). O-GlcNAcylation regulates a wide spectrum of substrates including many proteins involved in epigenetic modification. Like epigenetic modifications, abnormality of O-GlcNAcylation is also common in cancer. Studies have revealed substantial impact on HBP enzymes and OGT/OGA by oncogenic signals. In this review, we will first summarize how oncogenic signals regulate HBP enzymes, OGT and OGA in cancer. We will then integrate this knowledge with the up to date understanding how O-GlcNAcylation regulates epigenetic machinery. With this, we propose a signal axis from oncogenic signals through O-GlcNAcylation dysregulation to epigenetic abnormality in cancer. Further elucidation of this axis will not only advance our understanding of cancer biology but also provide new revenues towards cancer therapy.
m6A, a conserved and abundant modification on RNA, regulates RNA processing and function. RNA m6A machinery including writers, erasers, and readers of m6A is indispensable for m6A installation and function. Intriguingly, recent studies have revealed that m6A machinery can be recruited to chromatin by pleiotropic factors including nascent RNA, transcription factors, regulatory RNA, histone modifications, and epigenetic machinery. Consequently, recruitment of m6A machinery can directly regulate chromatin biology, such as transcription, DNA damage repair, and DNA recombination beyond installation of m6A on nascent mRNA. Here, we discuss recent evidences showing that m6A machinery is targeted to chromatin and the direct biological consequences along with the underlying mechanisms.
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