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Shih, M.

Publications and source records attributed to Shih, M..

2 recordsLinked to original sources
bioRxiv2021

Reprogramming the neuroblastoma epigenome with a mitochondrial uncoupler

Dysregulated DNA methylation is associated with poor prognosis in cancer patients, promoting tumorigenesis and therapeutic resistance1. DNA methyltransferase inhibitors (DNMTi) reduce DNA methylation and promote cancer cell differentiation, with two DNMTi already approved for cancer treatment2. However, these drugs rely on cell division to dilute existing methylation, thus the demethylation effects are achieved in a passive manner, limiting their application in slow-proliferating tumor cells. In this study we use a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to actively achieve global DNA demethylation. NEN treatment promotes DNA demethylation by activating electron transport chain (ETC) to produce -ketoglutarate (-KG), a substrate for the DNA demethylase TET. In addition, NEN inhibits reductive carboxylation, a key metabolic pathway to support growth of cancer cells with defective mitochondria or under hypoxia. Importantly, NEN treatment reduces 2-hydroxyglutarate (2-HG) generation and blocks DNA hypermethylation under hypoxia. Together, these metabolic reprogramming effects of NEN actively alter the global DNA methylation landscape and promote neuroblastoma differentiation. These results not only support Warburgs original hypothesis that inhibition of ETC causes cell de-differentiation and tumorigenesis, but also suggest that mitochondrial uncoupling is an effective metabolic and epigenetic intervention that remodels the tumor epigenome for better prognosis.

cancer biology↗
bioRxiv2021

The kpc-1 (furin) 3'UTR promotes dendritic transport and local translation of mRNAs to regulate dendrite branching and self-avoidance of a nociceptive neuron

A recently reported Schizophrenia-associated genetic variant in the 3UTR of the human furin gene, a homolog of C. elegans kpc-1, highlights an important role of the furin 3UTR in neuronal development(1). We isolate three kpc-1 mutants that display abnormal dendrite arborization in PVD neurons and defective male mating behaviors. We show that the kpc-1 3UTR participates in dendrite branching and self-avoidance. The kpc-1 3UTR facilitates mRNA localization to branching points and contact points between sibling dendrites and promotes local protein synthesis. We identify a secondary structural motif in the kpc-1 3UTR required for dendrite self-avoidance. Animals with dma-1 receptor over-expression exhibit similar dendrite branching and self-avoidance defects that are suppressed with kpc-1 over-expression. Our results support a model in which KPC-1 proteins are synthesized at branching points and contact points to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance of a mechanosensory neuron important for male courtship.

neuroscience↗