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

Ling Chen,Yongguang Tao,Bin Yan,Zanxian Xia,Yan Cheng,Xiaoli Liu,Ya Cao,Shuang Liu,Hu Zhou,Yating Liu,Weiwei Lai,Rui Yang,Zuli Wang,Ying Shi,Desheng Xiao,Na Liu

doi:10.1186/s13072-019-0302-9

Abstract

BackgroundThe 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.ResultsHere, 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.ConclusionThese 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.

Highlights

The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase mouse double minute homolog2 (MDM2)
lymphoid-specific helicase (LSH) does not alter the p53 messenger RNA (mRNA) level, but upregulates the protein level of p53 To address the potential role of LSH in p53 expression, we stably overexpressed LSH in two cell lines, CNE1-FLAG-LSH and HK1-FLAG-LSH, and we found that LSH drastically promoted levels of endogenous p53 and that p21, a target of p53, was induced by LSH in CNE1 and HK1 cells (Fig. 1a, b)
The knockdown approach successfully reduced LSH protein by more than 80% using two LSH-specific short hairpin RNAs, and we showed that stable knockdown of LSH dampened p53 protein levels (Fig. 1c)

Summary

Introduction

The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. P53 is a transcription factor controlling cellular metabolism, and it plays a key role in tumor suppression by Epigenetic alterations are increasingly implicated in cancer causation and progression, because chromatin functions in both the transcriptional regulation and the stability of genome [7, 8]. Epigenetic abnormalities are regarded as a hallmark of cancer, and commonly studied mechanisms include DNA methylation and associated DNA methyltransferases [9, 10]. For this reason, specific chromatin-modifying enzymes have been paid increasing attention in recent years, especially for they dynamically regulated histone modifications [11]. In promyelocytic leukemia (PML), sumoylation leads to senescence via a complex interconnected network of pathways involved in the sumoylation of proteins. p53/pRb and its interacting

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Discussion

Conclusion