Mutually exclusive expression of EZH2 and H3K27me3 in non-small cell lung carcinoma

Onishi, Takafumi; Takashima, Tsuyoshi; Kurashige, Masako; Ohshima, Kenji; Morii, Eiichi

doi:10.1016/j.prp.2022.154071

Cited by 3 publications

(3 citation statements)

References 16 publications

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“…Finally, while the co-expression of FOXP2 and EZH2 in patient samples may seem contradictory to the results from our mouse model, we believe these results support each other. Several papers, including our own, have shown an inverse correlation between EZH2 and its catalytic mark, H3K27me3 in vivo 6 – 9 , 41 – 43 . This abundant EZH2 may be part of PRC2-independent complexes 44 – 46 , or unable to complete histone methylation for a variety of reasons (one reason postulated is lack of SAM).…”

Section: Discussionmentioning

confidence: 77%

Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors

et al. 2023

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Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 could be suppressed by BET inhibition. Poorly differentiated human lung cancers were enriched for an H3K27me3-low state, representing a subtype that may benefit from BET inhibition as a single therapy or combined with additional EZH2 inhibition. These data highlight diverse roles of PRC2 in KRAS-driven lung adenocarcinomas, and demonstrate the utility of three-dimensional cultures for exploring epigenetic drug sensitivities for cancer.

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Section: Discussionmentioning

confidence: 77%

Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors

et al. 2023

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“…EZH2 is highly expressed in many tumors, including non-small cell lung carcinoma (NSCLC), and the higher expression of EZH2 is related to poor prognosis. 72 In contrast, H3K27me3 expression is lower in NSCLC than in normal lung tissue, and the high H3K27me3 expression level is related to a favorable prognosis. NSCLC usually consists of morphologically distinct tumor cells and is thereby classified into several subtypes, which are related to the aggressiveness of tumors.…”

Section: Genetic Mutations and Non-mutational Epigenetic Reprogrammingmentioning

confidence: 97%

“…The resultant trimethylated form of H3K27 (H3K27me3) repressively regulates gene expression and plays an important role in stem cell differentiation and early embryonic development. EZH2 is highly expressed in many tumors, including non‐small cell lung carcinoma (NSCLC), and the higher expression of EZH2 is related to poor prognosis 72 . In contrast, H3K27me3 expression is lower in NSCLC than in normal lung tissue, and the high H3K27me3 expression level is related to a favorable prognosis.…”

Section: Introductionmentioning

confidence: 99%

Tumor heterogeneity from the viewpoint of pathologists

Morii

2023

Pathology International

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Morphological and functional heterogeneity are found in tumors, with the latter reflecting the different levels of resistance against antitumor therapies. In a therapy‐resistant subpopulation, the expression levels of differentiation markers decrease, and those of immature markers increase. In addition, this subpopulation expresses genes involved in drug metabolism, such as aldehyde dehydrogenase 1A1 (ALDH1A1). Because of their similarity to stem cells, cells in the latter therapy‐resistant subpopulation are called cancer stem cells (CSCs). Like normal stem cells, CSCs were originally thought not to arise from non‐CSCs, but this hierarchical model is too simple. It is now believed that CSCs are generated from non‐CSCs. The plasticity of tumor phenotypes between CSCs and non‐CSCs causes difficulty in completely curing tumors. In this review, focusing on ALDH1A1 as a marker for CSCs or immature tumor cells, the dynamics of ALDH1A1‐expressing tumor cells and their regulatory mechanisms are described, and the plausible regulatory mechanisms of plasticity of ALDH1A1 expression phenotype are discussed. Genetic mutations are a significant factor for tumorigenesis, but non‐mutational epigenetic reprogramming factors yielding tumor heterogeneity are also crucial in determining tumor characteristics. Factors influencing non‐mutational epigenetic reprogramming in tumors are also discussed.

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