bims-ectoca 2024-01-07 papers

Issue of 2024‒01‒07
five papers selected by
Ankita Daiya, BITS Pilani

Oncogene. 2024 Jan 05.

Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers.

Marco Jessen, Dörthe Gertzmann, Franziska Liss, Franziska Zenk, Laura Bähner, Victoria Schöffler, Clemens Schulte, Hans Michael Maric, Carsten P Ade, Björn von Eyss, Stefan Gaubatz.

YAP activation in cancer is linked to poor outcomes, making it an attractive therapeutic target. Previous research focused on blocking the interaction of YAP with TEAD transcription factors. Here, we took a different approach by disrupting YAP's binding to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. MY-COMP induced cell cycle defects, nuclear abnormalities, and polyploidization. In an AKT and YAP-driven liver cancer model, MY-COMP significantly reduced liver tumorigenesis, highlighting the importance of the YAP-B-MYB interaction in tumor development. MY-COMP also perturbed the cell cycle progression of YAP-dependent uveal melanoma cells but not of YAP-independent cutaneous melanoma cell lines. It counteracted YAP-dependent expression of MMB-regulated cell cycle genes, explaining the observed effects. We also identified NIMA-related kinase (NEK2) as a downstream target of YAP and B-MYB, promoting YAP-driven transformation by facilitating centrosome clustering and inhibiting multipolar mitosis.

DOI: https://doi.org/10.1038/s41388-023-02926-w

Clin Epigenetics. 2024 Jan 03. 16(1): 8

Histone acetylation: a key determinant of acquired cisplatin resistance in cancer.

Abhiram Natu, Tripti Verma, Bharat Khade, Rahul Thorat, Poonam Gera, Sangita Dhara, Sanjay Gupta.

Cisplatin is an alkylating class of chemotherapeutic drugs used to treat cancer patients. However, cisplatin fails in long-term treatment, and drug resistance is the primary reason for tumor recurrence. Hence, understanding the mechanism of acquirement of chemoresistance is essential for developing novel combination therapeutic approaches. In this study, in vitro cisplatin-resistant cancer cell line models were developed. Gene ontology and GSEA of differentially expressed genes between parental and resistant cells suggest that PI3K-AKT signaling, central carbon metabolism, and epigenetic-associated phenomenon alter in cisplatin-resistant cells. Further, the data showed that increased glucose transport, alteration in the activity of histone-modifying enzymes, and acetyl-CoA levels in resistant cells paralleled an increase in global histone acetylation. Enrichment of histone acetylation on effectors of PI3K-AKT and glycolysis pathway provides evidence of epigenetic regulation of the key molecules in drug resistance. Moreover, cisplatin treatment to resistant cells showed no significant changes in histone acetylation marks since drug treatment alters cell epigenome. In continuation, targeting PI3K-AKT signaling and glycolysis leads to alteration in histone acetylation levels and re-sensitization of resistant cells to chemo-drug. The data provide evidence of histone acetylation's importance in regulating pathways and cisplatin-resistant cells' cell survival. Our study paves the way for new approaches for developing personalized therapies in affecting metabolic pathways and epigenetic changes to achieve better outcomes for targeting drug-resistant cells.

Keywords: 2DG; Cisplatin; Hyperacetylation; PI3K; Resistance

DOI: https://doi.org/10.1186/s13148-023-01615-5

Ann Clin Lab Sci. 2023 Nov;53(6): 920-930

Activation of HDAC8 Can Suppress the Proliferation of Osteosarcoma Cells via TP53 and STAT3/ERK Signaling Pathways.

Liangming Wang, Xiaoming Bai, Xiaolu Zhang, Xinwen Wang, Shiyuan Chen, Shiqiang Wu, Liang Lin.

OBJECTIVE: Osteosarcoma is the most common malignant bone cancer and is typically associated with poor prognosis. Histone deacetylase 8 (HDAC8) presents as an effective target in anti-tumor treatment in various tumors. As the functions of HDAC8 in osteosarcoma have not been studied thoroughly, our study aims to explore the effects of HDAC8 in osteosarcoma proliferation.METHODS: HDAC8 expression was analyzed in The Cancer Genome Atlas (TCGA)-pan-cancer dataset. The expression of HDAC8 in osteosarcoma cell lines was detected by western blot. TM-2-51, an activator of HDAC8, was taken to promote HDAC8 expression in osteosarcoma cells. Cell Counting Kit-8 (CCK-8) assay was applied to analyze cell viability changes and colony formation while 5-ethynyl-29-deoxyuridine (EdU) assays were used to evaluate cell proliferation. The migration and invasion abilities were analyzed by transwell assay, the distributions of cell cycle were analyzed by flow cytometry, and xenograft models were used to study the effect of HDAC8 activation in vivo. Furthermore, the mechanism underlying HDAC8's influence in osteosarcoma was analyzed by western blot assay.
RESULTS: Our study demonstrated that activation of HDAC8 in osteosarcoma cells can suppress cell viability, proliferation, migration, invasion, and arrest cell cycle of the osteosarcoma cells via TP53 and STAT3/ERK signaling pathway. Xenograft models confirmed that HDAC8 activation can reduce tumor growth in vivo.
CONCLUSION: The activation of HDCA8 could contribute negatively to osteosarcoma proliferation, and HDAC8 may represent a valuable therapeutic target in osteosarcoma therapy.

Keywords: HDAC8; activation; osteosarcoma; pathways; proliferation

Adv Sci (Weinh). 2023 Dec 31. e2305867

Coupling of Perinuclear Actin Cap and Nuclear Mechanics in Regulating Flow-Induced Yap Spatiotemporal Nucleocytoplasmic Transport.

Mechanical forces, including flow shear stress, govern fundamental cellular processes by modulating nucleocytoplasmic transport of transcription factors like Yes-associated Protein (YAP). However, the underlying mechanical mechanism remains elusive. In this study, it is reported that unidirectional flow induces biphasic YAP transport with initial nuclear import, followed by nuclear export as actin cap formation and nuclear stiffening. Conversely, pathological oscillatory flow induces slight actin cap formation, nuclear softening, and sustained YAP nuclear localization. To elucidate the disparately YAP spatiotemporal distribution, a 3D mechanochemical model is developed, which integrates flow sensing, cytoskeleton organization, nucleus mechanotransduction, and YAP transport. The results unveiled that despite the significant localized nuclear stress imposed by the actin cap, its inherent stiffness counteracts the dispersed contractile stress exerted by conventional fibers on the nuclear membrane. Moreover, alterations in nuclear stiffness synergistically regulate nuclear deformation, thereby governing YAP transport. Furthermore, by expanding the single-cell model to a collective vertex framework, it is revealed that the irregularities in actin cap formation within individual cells have the potential to induce topological defects and spatially heterogeneous YAP distribution in the cellular monolayer. This work unveils a unified mechanism of flow-induced nucleocytoplasmic transport, providing a linkage between transcription factor localization and mechanical stimulation.

Keywords: YAP; flow shear stress; mechanochemical modeling; mechanotransduction; perinuclear actin cap

DOI: https://doi.org/10.1002/advs.202305867

Theranostics. 2024 ;14(2): 593-607

Combined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1.

Rui Hu, Huihui Hou, Yao Li, Minghui Zhang, Xin Li, Yanzhong Chen, Ying Guo, Hongyin Sun, Shuang Zhao, Mengting Liao, Dongsheng Cao, Qin Yan, Xiang Chen, Mingzhu Yin.

Rationale: The response rate to the MEK inhibitor trametinib in BRAF-mutated melanoma patients is less than 30%, and drug resistance develops rapidly, but the mechanism is still unclear. Yes1-associated transcriptional regulator (YAP1) is highly expressed in melanoma and may be related to MEK inhibitor resistance. The purpose of this study was to investigate the mechanism of YAP1 in MEK inhibitor resistance in melanoma and to screen YAP1 inhibitors to further determine whether YAP1 inhibition reverses MEK inhibitor resistance. Methods: On the one hand, we analyzed paired melanoma and adjacent tissue samples using RNA-seq and found that the Hippo-YAP1 signaling pathway was the top upregulated pathway. On the other hand, we evaluated the transcriptomes of melanoma samples from patients before and after trametinib treatment and investigated the correlation between YAP1 expression and trametinib resistance. Then, we screened for inhibitors that repress YAP1 expression and investigated the mechanisms. Finally, we investigated the antitumor effect of YAP1 inhibition combined with MEK inhibition both in vitro and in vivo. Results: We found that YAP1 expression levels upon trametinib treatment in melanoma patients were correlated with resistance to trametinib. YAP1 was translocated into the nucleus after trametinib treatment in melanoma cells, which could render resistance to MEK inhibition. Thus, we screened for inhibitors that repress YAP1 expression and identified multiple bromodomain and extra-terminal (BET) inhibitors, including NHWD-870, as hits. BET inhibition repressed YAP1 expression by decreasing BRD4 binding to the YAP1 promoter. Consistently, YAP1 overexpression was sufficient to reverse the proliferation defect caused by BRD4 depletion. In addition, the BET inhibitor NHWD-870 acted synergistically with trametinib to suppress melanoma growth in vitro and in vivo. Conclusions: We identified a new vulnerability for MEK inhibitor-resistant melanomas, which activated Hippo pathway due to elevated YAP1 activity. Inhibition of BRD4 using BET inhibitors suppressed YAP1 expression and led to blunted melanoma growth when combined with treatment with the MEK inhibitor trametinib.

Keywords: BET inhibitor; BRD4; MEK inhibitor; Melanoma; YAP1

DOI: https://doi.org/10.7150/thno.85437