Aberrant Splicing, Hyaluronan Synthases and Intracellular Hyaluronan as Drivers of Oncogenesis and Potential Drug Targets
Patrick M. Pilarski,
Andrew R. Belch,
Linda M. Pilarski.
Current evidence suggests a significant role of aberrant splicing in the development and maintenance of
malignancy. This multistep, tightly regulated epigenetic process leads to the production of abnormal proteins with
abnormal functions contributing to underlying mechanisms of malignant transformation. Splicing patterns in malignant
cells can be altered not only by the mutations detected on the aberrantly spliced gene, but also by the mutations detected
on the genes encoding splicing factors. For example, aberrant pre-mRNA splicing, leading to intracellular or extracellular
HA synthesis by HASs, contributes to the initiation and progression of various types of cancer. The influence of
intracellular HA appears to be particularly significant and is promoted by aberrant splicing. In this review we report a
model describing oncogenic potential of aberrant splicing, with a focus on HAS1 and intracellular HA. We also suggest
that the influence of splicing mutations on malignant disease is likely multifactorial. For the triple axis of HA, HAS1 and
RHAMM, mutations in HAS1 provide an indicator that these aberrations contribute to the events that lead to malignancy
through increased risk and predisposition. Here, we also summarize the impact of splicing abnormalities on cancer and the
possible oncogenic impact of aberrantly spliced HAS1. In conclusion, we emphasize that specific gene splice variants and
the splicing process itself offer potential targets for novel drug treatment strategies.
Keywords: Alternative splicing, drug targets, hyaluronan, hyaluronan synthases, oncogenesis.
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