DNA methylation modifier LSH inhibits p53 ubiquitination and transactivates p53 to promote lipid metabolism.

The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifier lymphoid-specific helicase (LSH) is essential for DNA methylation and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifiers and transcription factors remains largely unknown.Here, we ...
present data suggesting that LSH regulates p53 in cis through two pathways: prevention proteasomal degradation through its deubiquitination, which is achieved by reducing the lysine 11-linked, lysine 48-linked polyubiquitin chains (K11 and K48) on p53; and revival of the transcriptional activity of p53 by forming a complex with PKM2 (pyruvate kinase 2). Furthermore, we confirmed that the LSH-PKM2 interaction occurred at the intersubunit interface region of the PKM2 C-terminal region and the coiled-coil domains (CC) and ATP-binding domains of LSH, and this interaction regulated p53-mediated transactivation in cis in lipid metabolism, especially lipid catabolism.These findings suggest that LSH is a novel regulator of p53 through the proteasomal pathway, thereby providing an alternative mechanism of p53 involvement in lipid metabolism in cancer.
Mesh Terms:
Carrier Proteins, Cell Line, Tumor, DNA Helicases, DNA Methylation, Humans, Leupeptins, Lipid Metabolism, Membrane Proteins, Proto-Oncogene Proteins c-mdm2, RNA Interference, RNA, Small Interfering, Regulatory Elements, Transcriptional, Thyroid Hormones, Transcriptional Activation, Tumor Suppressor Protein p53, Ubiquitination
Epigenetics Chromatin
Date: Dec. 08, 2018
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