bims-ectoca 2022-06-05 papers

Issue of 2022‒06‒05
six papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Biochem Pharmacol. 2022 May 28. pii: S0006-2952(22)00204-0. [Epub ahead of print] 115110

Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers.

Libo Xu, Jinghua Zhang, Jicheng Sun, Kunlin Hou, Chenxin Yang, Ying Guo, Xiaorui Liu, Dhan V Kalvakolanu, Ling Zhang, Baofeng Guo.

The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.

Keywords: autophagy; cancer stem cells; drug resistance; epigenetics; quiescence; tumor heterogeneity

DOI: https://doi.org/10.1016/j.bcp.2022.115110

Oncogene. 2022 Jun 02.

Enhancer methylation dynamics drive core transcriptional regulatory circuitry in pan-cancer.

Xu Pan, Xin Li, Jie Sun, Zhiying Xiong, Haoyu Hu, Shangwei Ning, Hui Zhi.

Accumulating evidence has demonstrated that enhancer methylation has strong and dynamic regulatory effects on gene expression. Some transcription factors (TFs) can auto- and cross-regulate in a feed-forward manner, and cooperate with their enhancers to form core transcriptional regulatory circuitries (CRCs). However, the elaborated regulatory mechanism between enhancer methylation and CRC remains the tip of the iceberg. Here, we revealed that DNA methylation could drive the tissue-specific enhancer basal transcription and target gene expression in human cancers. By integrating methylome, transcriptome, and 3D genomic data, we identified enhancer methylation triplets (enhancer methylation-enhancer transcription-target gene expression) and dissected potential regulatory patterns within them. Moreover, we observed that cancer-specific core TFs regulated by enhancers were able to shape their enhancer methylation forming the enhancer methylation-driven CRCs (emCRCs). Further parsing of clinical implications showed rewired emCRCs could serve as druggable targets and prognostic risk markers. In summary, the integrative analysis of enhancer methylation regulome would facilitate portraying the cancer epigenomics landscape and developing the epigenetic anti-cancer approaches.

DOI: https://doi.org/10.1038/s41388-022-02359-x

Eur J Cell Biol. 2022 May 20. pii: S0171-9335(22)00041-3. [Epub ahead of print]101(3): 151238

The PRC2 molecule EED is a target of epigenetic therapy for neuroblastoma.

Dilibaerguli Shaliman, Hisanori Takenobu, Ryuichi P Sugino, Miki Ohira, Takehiko Kamijo.

Epigenetic modifications by polycomb repressive complex (PRC) molecules appear to play a role in the tumorigenesis and aggressiveness of neuroblastoma (NB). Embryonic ectoderm development (EED) is a member of the PRC2 complex that binds to the H3K27me3 mark deposited by EZH2 via propagation on adjacent nucleosomes. We herein investigated the molecular roles of EED in MYCN-amplified NB cells using EED-knockdown (KD) shRNAs, EED-knockout sgRNAs, and the EED small molecule inhibitor EED226. The suppression of EED markedly inhibited NB cell proliferation and flat and soft agar colony formation. A transcriptome analysis using microarrays of EED-KD NB cells indicated the de-repression of cell cycle-regulated and differentiation-related genes. The results of a GSEA analysis suggested that inhibitory cell cycle-regulated gene sets were markedly up-regulated. Furthermore, an epigenetic treatment with the EED inhibitor EED226 and the HDAC inhibitors valproic acid/SAHA effectively suppressed NB cell proliferation and colony formation. This combined epigenetic treatment up-regulated cell cycle-regulated and differentiation-related genes. The ChIP sequencing analysis of histone codes and PRC molecules suggested an epigenetic background for the de-repression of down-regulated genes in MYCN-amplified/PRC2 up-regulated NB.

Keywords: EED; Histone code; Neuroblastoma; Polycomb

DOI: https://doi.org/10.1016/j.ejcb.2022.151238

Semin Cancer Biol. 2022 May 25. pii: S1044-579X(22)00124-9. [Epub ahead of print]

Long Non-Coding RNA and RNA-Binding Protein Interactions in Cancer: Experimental and Machine Learning Approaches.

Hibah Shaath, Radhakrishnan Vishnubalaji, Ramesh Elango, Ahmed Kardousha, Zeyaul Islam, Rizwan Qureshi, Tanvir Alam, Prasanna R Kolatkar, Nehad M Alajez.

Understanding the complex and specific roles played by non-coding RNAs (ncRNAs), which comprise the bulk of the genome, is important for understanding virtually every hallmark of cancer. This large group of molecules plays pivotal roles in key regulatory mechanisms in various cellular processes. Regulatory mechanisms, mediated by long non-coding RNA (lncRNA) and RNA-binding protein (RBP) interactions, are well documented in several types of cancer. Their effects are enabled through networks affecting lncRNA and RBP stability, lncRNA metabolism including N6-methyladenosine (m6A) and alternative splicing, subcellular localization, and numerous other mechanisms involved in cancer. In this review, we discuss the reciprocal interplay between lncRNAs and RBPs and their involvement in epigenetic regulation via histone modifications, as well as their key role in resistance to cancer therapy. Other aspects of RBPs including their structural domains, provide a deeper knowledge on how lncRNAs and RBPs interact and exert their biological functions. In addition, current state-of-the-art knowledge, facilitated by machine and deep learning approaches, unravels such interactions in better details to further enhance our understanding of the field, and the potential to harness RNA-based therapeutics as an alternative treatment modality for cancer are discussed.

Keywords: RBP, lncRNA-protein interaction (LPI); cancer; deep learning; lncRNA, RNA-binding protein; long non-coding RNA; machine learning; mechanisms of action; structural and functional domains

DOI: https://doi.org/10.1016/j.semcancer.2022.05.013

Redox Biol. 2022 May 18. pii: S2213-2317(22)00116-1. [Epub ahead of print]53 102344

TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling.

Wei Liu, Yuechao Zhao, Guangfu Wang, Shuang Feng, Xuhui Ge, Wu Ye, Zhuanghui Wang, Yufeng Zhu, Weihua Cai, Jianling Bai, Xuhui Zhou.

Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.

Keywords: Autophagic cell death; Osteosarcoma; ROS; TRIM22/NRF2; Warburg effect

DOI: https://doi.org/10.1016/j.redox.2022.102344

Drug Res (Stuttg). 2022 May 30.

Melatonin Increases the Sensitivity of Osteosarcoma Cells to Chemotherapy Drug Cisplatin.

Foroogh Hosseini, Dariush Shanehbandi, Jafar Soleimanpour, Bahman Yousefi, Forough Alemi.

Chemotherapy, which is one of the common treatments for osteosarcoma (OS), has many side effects and in some cases has low effectiveness due to chemoresistance, hence it is vital to study new therapies for OS. In this regard, we combined melatonin with cisplatin and evaluate their effect on MG63 OS cells. Since melatonin has anti-cancer properties, we hypothesized that its combination with cisplatin could increase the effectiveness of cisplatin. Firstly, MTT assay was used to evaluate the cell viability and cytotoxicity of cisplatin on MG63 cells and the results showed that melatonin in combination with cisplatin increases the sensitivity of MG63 cells to cisplatin. In addition, qRT-PCR results showed that the expressions of miR-181 and P53, CYLD, CBX7 and BCL2 genes change in MG63 cells after treatment with the combination of cisplatin and melatonin, so that the expression of P53, CYLD and CBX7 increased and the expression of BCL2 and miR-181b decreases significantly. Furthermore, analysis of Annexin V/FITC assay data revealed that the rate of apoptosis in MG63 OS cell line remarkably promoted after treated with cisplatin and melatonin combination. As a result, our findings show that melatonin in combination with cisplatin increases the effectiveness of cisplatin in osteosarcoma cells and this study provides a new therapeutic approach for OS.

DOI: https://doi.org/10.1055/a-1830-8716