bims-ectoca 2023-10-08 papers

MedComm (2020). 2023 Oct;4(5): e375

Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential.

As highly conserved among diverse species, Hippo signaling pathway regulates various biological processes, including development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size. Studies in the last two decades have provided a good framework for how these fundamental functions of Hippo signaling are tightly regulated by a network with numerous intracellular and extracellular factors. The Hippo signaling pathway, when dysregulated, may lead to a wide variety of diseases, especially cancer. There is growing evidence demonstrating that dysregulated Hippo signaling is closely associated with tumorigenesis, cancer cell invasion, and migration, as well as drug resistance. Therefore, the Hippo pathway is considered an appealing therapeutic target for the treatment of cancer. Promising novel agents targeting the Hippo signaling pathway for cancers have recently emerged. These novel agents have shown antitumor activity in multiple cancer models and demonstrated therapeutic potential for cancer treatment. However, the detailed molecular basis of the Hippo signaling-driven tumor biology remains undefined. Our review summarizes current advances in understanding the mechanisms by which Hippo signaling drives tumorigenesis and confers drug resistance. We also propose strategies for future preclinical and clinical development to target this pathway.

Keywords: drug resistance; epigenetic; hippo signaling; metabolism; target therapy; tumorigenesis

DOI: https://doi.org/10.1002/mco2.375

BMC Cancer. 2023 Oct 03. 23(1): 935

LRPPRC regulates malignant behaviors, protects mitochondrial homeostasis, mitochondrial function in osteosarcoma and derived cancer stem-like cells.

Ziyi Zhao, Yingwei Sun, Jing Tang, Yuting Yang, Xiaochao Xu.

BACKGROUND: Leucine-rich pentatricopeptide repeat containing (LRPPRC) is a potential oncogene in multiple tumor types, including lung adenocarcinoma, esophageal squamous cell carcinoma and gastric cancer. LRPPRC exerts its tumor-promoting effects mainly by regulating mitochondrial homeostasis and inducing oxidative stress. However, the exact role and mechanisms by which LRPPRC acts in osteosarcoma and osteosarcoma-derived cancer stem-like cells (CSCs), which potentially critically contribute to recurrence, metastasis and chemoresistance, are still largely unclear.
METHODS: LRPPRC level in osteosarcoma cells and CSCs were detected by western blot. Effects of LRPPRC on CSCs were accessed after LRPPRC knockdown by introducing lentivirus containing shRNA targeting to LRPPRC mRNA.
RESULTS: we found that LRPPRC was highly expressed in several osteosarcoma cell lines and that LRPPRC knockdown inhibited malignant behaviors, including proliferation, invasion, colony formation and tumor formation, in MG63 and U2OS cells. Enriched CSCs derived from MG63 and U2OS cells presented upregulated LRPPRC levels compared to parental cells (PCs), and LRPPRC knockdown markedly decreased the sphere-forming capacity. These findings demonstrate that LRPPRC knockdown decreased stemness in CSCs. Consistent with a previous report, LRPPRC knockdown decreased the expression levels of FOXM1 and its downstream target genes, including PRDX3, MnSOD and catalase, which are responsible for scavenging reactive oxygen species (ROS). Expectedly, LRPPRC knockdown increased the accumulation of ROS in osteosarcoma and osteosarcoma-derived CSCs under hypoxic conditions due to the decrease in ROS scavenging proteins. Moreover, LRPPRC knockdown sensitized osteosarcomas and CSCs against carboplatin, a ROS-inducing chemoagent, and promoted apoptosis. Furthermore, LRPPRC knockdown significantly decreased the mitochondrial membrane potential, disturbed mitochondrial homeostasis and led to mitochondrial dysfunction.
CONCLUSION: Taken together, these findings indicated that LRPPRC exerts critical roles in regulating mitochondrial homeostasis, mitochondrial function and tumorigenesis in osteosarcomas and osteosarcoma-derived CSCs. This suggests that LRPPRC might be a promising therapeutic target for osteosarcomas.

Keywords: Cancer stem-like cells; FOXM1; LRPPRC; Mitochondrial homeostasis; Osteosarcoma

DOI: https://doi.org/10.1186/s12885-023-11443-8

Toxicol Res. 2023 Oct;39(4): 711-719

YPEL3 expression induces cellular senescence via the Hippo signaling pathway in human breast cancer cells.

Yeonju Kwon, Hyein Lee, Hyemin Park, Boyoung Lee, Tae-Uk Kwon, Yeo-Jung Kwon, Young-Jin Chun.

The Hippo pathway is a signaling pathway that controls organ size in animals by regulating cell proliferation and apoptosis. Yes-associated protein 1 (YAP1), an oncogene associated with the development and progression of breast cancer, is downregulated by the Hippo pathway and is associated with the development and progression of breast cancer. Yippee-like 3 (YPEL3) is a target gene of the tumor suppressor protein p53, and its activation has been shown to inhibit cell growth, induce cellular senescence, and suppress tumor cell metastasis. In this study, we found that YAP1 inhibits the expression of YPEL3 expression in breast cancer cells. Furthermore, a decrease in lamin B1, a marker protein of cellular senescence, coupled with the activation of senescence-associated β-galactosidase indicated that upregulating YPEL3 levels through YAP1 downregulation can induce cellular senescence. Additionally, elevated YPEL3 levels resulted in higher levels of oxygen consumption rate in mitochondria, thus promoting apoptosis. This suggests that YPEL3 plays a crucial role in regulating oxidative stress and cell apoptosis in breast cancer cells. Therefore, the interaction between YAP1 and YPEL3 represents a novel mechanism of cellular senescence mediated by the Hippo signaling pathway. Collectively, our findings suggest that the Hippo signaling pathway plays an important role in regulating cellular senescence, which could have implications for the development of new therapeutic strategies for diseases such as cancer.

Keywords: Cellular senescence; Hippo signaling pathway; YAP1; YPEL3

DOI: https://doi.org/10.1007/s43188-023-00208-x

bioRxiv. 2023 Sep 22. pii: 2023.09.21.558912. [Epub ahead of print]

Inter-organellar nucleic acid communication by a mitochondrial tRNA regulates nuclear metabolic transcription.

Christopher Rouya, King Faisal Yambire, Mark L Derbyshire, Hanan Alwaseem, Sohail F Tavazoie.

Efficient communication between mitochondria and the nucleus underlies homoeostatic metabolic control, though the involved mitochondrial factors and their mechanisms are poorly defined. Here, we report the surprising detection of multiple mitochondrial-derived transfer RNAs (mito-tRNAs) within the nuclei of human cells. Focused studies of nuclear-transported mito-tRNA-asparagine (mtAsn) revealed that its cognate charging enzyme (NARS2) is also present in the nucleus. MtAsn promoted interaction of NARS2 with histone deacetylase 2 (HDAC2), and repressed HDAC2 association with specific chromatin loci. Perturbation of this axis using antisense oligonucleotides promoted nucleotide biogenesis and enhanced breast cancer growth, and RNA and nascent transcript sequencing demonstrated specific alterations in the transcription of nuclear genes. These findings uncover nucleic-acid mediated communication between two organelles and the existence of a machinery for nuclear gene regulation by a mito-tRNA that restricts tumor growth through metabolic control.
Highlights: Multiple mitochondrial-derived tRNAs are detected in human cell nucleiMtAsn promotes binding between NARS2 and HDAC2Metabolic alterations driven by mtAsn impact cell proliferationMtAsn inhibition releases HDAC2 to bind and transcriptionally regulate multiple nuclear genes.

DOI: https://doi.org/10.1101/2023.09.21.558912

bioRxiv. 2023 Jul 23. pii: 2023.07.20.549955. [Epub ahead of print]

Predicting gene expression changes upon epigenomic drug treatment.

Piyush Agrawal, Vishaka Gopalan, Sridhar Hannenhalli.

Background: Tumors are characterized by global changes in epigenetic changes such as DNA methylation and histone modifications that are functionally linked to tumor progression. Accordingly, several drugs targeting the epigenome have been proposed for cancer therapy, notably, histone deacetylase inhibitors (HDACi) such as Vorinostatis and DNA methyltransferase inhibitors (DNMTi) such as Zebularine . However, a fundamental challenge with such approaches is the lack of genomic specificity, i.e., the transcriptional changes at different genomic loci can be highly variable thus making it difficult to predict the consequences on the global transcriptome and drug response. For instance, treatment with DNMTi may upregulate the expression of not only a tumor suppressor but also an oncogene leading to unintended adverse effect.
Methods: Given the pre-treatment transcriptome and epigenomic profile of a sample, we assessed the extent of predictability of locus-specific changes in gene expression upon treatment with HDACi using machine learning.
Results: We found that in two cell lines (HCT116 treated with Largazole at 8 doses and RH4 treated with Entinostat at 1µM) where the appropriate data (pre-treatment transcriptome and epigenome as well as post-treatment transcriptome) is available, our model distinguished the post-treatment up versus downregulated genes with high accuracy (up to ROC of 0.89). Furthermore, a model trained on one cell line is applicable to another cell line suggesting generalizability of the model.
Conclusions: Here we present a first assessment of the predictability of genome-wide transcriptomic changes upon treatment with HDACi. Lack of appropriate omics data from clinical trials of epigenetic drugs currently hampers the assessment of applicability of our approach in clinical setting.

DOI: https://doi.org/10.1101/2023.07.20.549955

Acta Biomater. 2023 Sep 29. pii: S1742-7061(23)00577-9. [Epub ahead of print]

Redox-Active Polyphenol Nanoparticles Deprive Endogenous Glutathione of Electrons for ROS Generation and Tumor Chemodynamic Therapy.

Yifei Wang, Jia Wang, Yunke Jiao, Kangli Chen, Tianhao Chen, Xin-Ping Wu, Xingwu Jiang, Wenbo Bu, Changsheng Liu, Xue Qu.

Chemodynamic therapy (CDT) based on generating reactive oxygen species (ROS) is promising for cancer treatment. However, the intrinsic H2O2 is deficient for CDT, and glutathione (GSH) eliminates ROS to protect tumor cells from ROS cytotoxicity. Herein, we propose a strategy to switch the electron flow direction of GSH for O2 reduction and ROS generation rather than ROS clearance by using P(DA-Fc) nanoparticles, which are polymerized from ferrocenecarboxylic acid (Fc) coupled dopamine. P(DA-Fc) NPs with phenol-quinone conversion ability mimic NOX enzyme to deprive electrons from GSH to reduce O2 for H2O2 generation; the following •OH release can be triggered by Fc. Semiquinone radicals in P(DA-Fc) are significantly enhanced after GSH treatment, further demonstrated with strong single-electron reduction ability by calculation. In vitro and in vivo experiments indicate that P(DA-Fc) can consume intrinsic GSH to produce endogenous ROS; ROS generation strongly depends on GSH/pH level and eventually causes tumor cell death. Our work makes the first attempt to reverse the function of GSH from ROS scavenger to ROS producer, explores new roles of PDA-based nanomaterials in CDT beyond photothermal reagents and drug carriers, and provides a new strategy to improve the efficiency of CDT. STATEMENT OF SIGNIFICANCE: P(DA-Fc) nanoparticles performing tumor microenvironment response capacity and tumor reductive power utilize ability were fabricated for CDT tumor suppression. After endocytosis by tumor cells, P(DA-Fc) deprived GSH of electrons for H2O2 and •OH release, mimicking the intrinsic ROS production conducted by NADPH, further inducing tumor cell necrosis and apoptosis. Our work makes the first attempt to reverse the function of GSH from ROS scavenger to producer, explores new functions of PDA-based nanomaterials in CDT beyond photothermal reagents and drug carriers, and provides a new strategy to improve CDT efficiency.

Keywords: GSH function reverse; NOX enzyme-like ROS generator; electron transporting; polyphenol-based CDT nanomaterial; redox activity

DOI: https://doi.org/10.1016/j.actbio.2023.09.037