Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

Abstract

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

“…U2OS shRNA p53 knockdown and shRNA control cells were generated using a lentivirus shRNA knockdown vector system. Lentiviral particles containing shRNAs targeting p53 (pLKO-p53-shRNA-427; Addgene #25636 and pLKO-p53-shRNA-941; Addgene #25637) [34] as well as control shRNAs (pLKO.pig Luc shRNA and pLKO.pig control shRNA1) [35,36] were produced in HEK293T cells and subsequently delivered to isogenic U2OS wild-type or MDM2 W329G cells following Addgene pLKO.1 Protocol. 2 µg/ml of puromycin was added to the transduced plates two days after infection for selecting stable clones.…”

Modeling RET-Rearranged Non-Small Cell Lung Cancer (NSCLC): Generation of Lung Progenitor Cells (LPCs) from Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

“…Although, the generation of iPSCs carrying hereditary mutations is a more attainable objective due to their presence in all cells of an individual, it enables the utilization of existing reprogramming protocols [21]. Several studies have already used patient-derived iPSCs carrying mutations, such as p53 or RB1 mutations, to elucidate mechanisms related to cancer [23,28]. However, to the best of our knowledge, there are presently no NSCLC patient-derived iPS cell lines and therefore no model of a patient-derived-iPSC lung cancer model.…”