bims-ectoca 2023-05-14 papers

Med Oncol. 2023 May 06. 40(6): 167

The roles of EZH2 in cancer and its inhibitors.

The enhancer of zeste homolog 2 (EZH2) is encoded by the Enhancer of zeste 2 polycomb repressive complex 2 subunit gene. EZH2 is involved in the cell cycle, DNA damage repair, cell differentiation, autophagy, apoptosis, and immunological modulation. The main function of EZH2 is to catalyze the methylation of H3 histone of H3K27Me3, which inhibits the transcription of target genes, such as tumor suppressor genes. EZH2 also forms complexes with transcriptions factors or directly binds to the promoters of target genes, leading to regulate gene transcriptions. EZH2 has been as a prominent target for cancer therapy and a growing number of potential targeting medicines have been developed. This review summarized the mechanisms that EZH2 regulates gene transcription and the interactions between EZH2 and important intracellular signaling molecules (Wnt, Notch, MEK, Akt) and as well the clinical applications of EZH2-targeted drugs.

Keywords: Cancer treatment; EZH2; Histone methylation; PRC2; Signal pathways

DOI: https://doi.org/10.1007/s12032-023-02025-6

Biochem Soc Trans. 2023 May 12. pii: BST20220983. [Epub ahead of print]

Studying histone inheritance in different systems using imaging-based methods and perspectives.

Emily Zion, Xin Chen.

Understanding cell identity is critically important in the fields of cell and developmental biology. During cell division, a mother cell duplicates the genetic material and cellular components to give rise to two daughter cells. While both cells receive the same genetic information, they can take on similar or different cell fates, resulting from a symmetric or asymmetric division. These fates can be modulated by epigenetic mechanisms that can alter gene expression without changing genetic information. Histone proteins, which wrap DNA into fundamental units of chromatin, are major carriers of epigenetic information and can directly influence gene expression and other cellular functions through their interactions with DNA. While it has been well studied how the genetic information is duplicated and segregated, how epigenetic information, such as histones, are inherited through cell division is still an area of investigation. Since canonical histone proteins are incorporated into chromatin during DNA replication and can be modified over time, it is important to study their inheritance within the context of the cell cycle. Here, we outline the biological basis of histone inheritance as well as the imaging-based experimental design that can be used to study this process. Furthermore, we discuss various studies that have investigated this phenomenon with the focus on asymmetrically dividing cells in different systems. This synopsis provides insight into histone inheritance within the context of the cell cycle, along with the technical methods and considerations that must be taken when studying this process in vivo.

Keywords: epigenetics; histones; stem cells

DOI: https://doi.org/10.1042/BST20220983

Int J Cancer. 2023 May 10.

GSK-J4: An H3K27 histone demethylase inhibitor, as a potential anti-cancer agent.

Nidhi Dalpatraj, Ankit Naik, Noopur Thakur.

Aberrant epigenetic modifications are emerging as potent drivers of tumor initiation and progression. The deregulation of H3K27me3 marks has shown to play an important role in cancer progression in several cancers. The H3K27me3 mark is associated with gene silencing. The reversible nature of these epigenetic aberrations makes them an important target for treating cancer. GSK-J4 is a histone demethylase inhibitor that inhibits the JMJD3/UTX enzyme, which results in the upregulation of H3K27me3 levels. In this review, the anti-cancer properties of GSK-J4 have been summarized, the various molecular pathways targeted, in-vivo studies, and drug combination studies in different cancer models. GSK-J4 targeted pathways like apoptosis, cell cycle, invasion, migration, DNA damage repair, metabolism, oxidative stress, stemness, etc. GSK-J4 is a promising candidate alone and in combination with other conventional anti-cancer drugs against different cancer types.

Keywords: GSK-J4; In-vivo studies; cancer; combinatorial studies; histone modifications

DOI: https://doi.org/10.1002/ijc.34559

Front Oncol. 2023 ;13 1196448

Editorial: Altered epigenetic modification mediated dysregulated transcriptional networks in drug resistance.

Bryce Brunetti, Akihiro Yoshida.

Keywords: cancer; drug resistance; dysregulated transcription; epigenetic; epigenetic modification; transcriptional network

DOI: https://doi.org/10.3389/fonc.2023.1196448

Int J Biol Sci. 2023 ;19(7): 2289-2303

Deubiquitinase USP13 regulates glycolytic reprogramming and progression in osteosarcoma by stabilizing METTL3/m6A/ATG5 axis.

Ce Wang, Yichen Meng, Jianquan Zhao, Jun Ma, Yuechao Zhao, Rui Gao, Wei Liu, Xuhui Zhou.

Reprogramming metabolism is a hallmark of cancer cells for rapid progression. However, the detailed functional role of deubiquitinating enzymes (DUBs) in tumor glycolytic reprogramming is still unknown and requires further investigation. USP13 was found to upregulate in osteosarcoma (OS) specimens and promote OS progression through regulating aerobic glycolysis. Interestingly, the m6A writer protein, METTL3, has been identified as a novel target of USP13. USP13 interacts with, deubiquitinates, and therefore stabilizes METTL3 at K488 by removing K48-linked ubiquitin chains. Since METTL3 is a well-known m6A writer and USP13 stabilizes METTL3, we further found that USP13 increased global m6A abundance in OS cells. The results of RNA sequencing and methylated RNA immunoprecipitation sequencing indicated METTL3 could bind to m6A-modified ATG5 mRNA, which is crucial for autophagosome formation, and inhibit ATG5 mRNA decay on an IGF2BP3 dependent manner, thereby promoting autophagy and the autophagy-associated malignancy of OS. Using a small-molecule inhibitor named Spautin-1 to pharmacologically inhibit USP13 induced METTL3 degradation and exhibited significant therapeutic efficacy both in vitro and in vivo. Collectively, our study results indicate that USP13 promotes glycolysis and tumor progression in OS by stabilizing METTL3, thereby stabilizing ATG5 mRNA and facilitating autophagy in OS. Our findings demonstrate the role of the USP13-METTL3-ATG5 cascade in OS progression and show that USP13 is a crucial DUB for the stabilization of METTL3 and a promising therapeutic target for treating OS.

Keywords: ATG5; METTL3; N6-methyladenosine; USP13; glycolytic reprogramming

DOI: https://doi.org/10.7150/ijbs.82081

Int J Biol Sci. 2023 ;19(7): 2034-2052

S100 Calcium Binding Protein A16 Promotes Cell Proliferation by triggering LATS1 ubiquitin degradation mediated by CUL4A ligase to inhibit Hippo pathway in Glioma development.

Yifang Hu, Rihua Zhang, Shan Lu, Wensong Zhang, Dan Wang, Yaoqi Ge, Feng Jiang, Xiaoxuan Qin, Yun Liu.

Background: S100 Calcium Binding Protein A16 (S100A16), a novel member of S100 protein family, is linked to tumorigenic processes and abundantly expressed in CNS tissues. Our study aimed to explore the biological function and possible mechanism of S100A16 in the progression of glioma. Methods: Sequence data of S100A16 and survival prognosis of glioma patients were initially analyzed using public databases. Glioma tissues were collected to examine S100A16 expression levels. Glioma cell lines and nude mice were subjected to in vitro and in vivo functional experiments. Western blot, immunofluorescence (IF), immunoprecipitation (IP) and ubiquitination assays were done to further elucidate the underlying mechanism. Results: This study firstly revealed that S100A16 was markedly up-regulated in glioma, and patients with higher S100A16 levels have a shorter survival time. S100A16 overexpression promoted the proliferation, invasion and migration of glioma cells, and the tumor formation of nude mice. Importantly, we identified S100A16 as a negative regulator of the Hippo pathway which could decrease LATS1 expression levels, promote the YAP nuclear import and initiate the downstream target genes CYR61 and CTGF. Moreover, our data showed that S100A16 destabilized LATS1 protein by inducing the CUL4A-mediated LATS1 ubiquitination degradation. Conclusions: This study demonstrated a vital biological role of S100A16 in glioma progression mechanism by promoting CUL4A-mediated LATS1 ubiquitination to inhibit Hippo signaling pathway. S100A16 could be a novel biomarker and treatment option for glioma patients.

Keywords: Hippo pathway; LATS1; S100A16; glioma; tumor progression

DOI: https://doi.org/10.7150/ijbs.79924