bims-ectoca 2024-03-24 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024–03–24
eight papers selected by
Ankita Daiya, Birla Institute of Technology and Science

YAP upregulates AMPKα1 to induce cancer cell senescence.
The molecular crosstalk of the hippo cascade in breast cancer: A potential central susceptibility.
Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics.
Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance.
The p53-mediated cell cycle regulation is a potential mechanism for emodin-suppressing osteosarcoma cells.
Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma.
N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer.
Non-coding RNA transcripts, incredible modulators of cisplatin chemo-resistance in bladder cancer through operating a broad spectrum of cellular processes and signaling mechanism.

Int J Biochem Cell Biol. 2024 Mar 16. pii: S1357-2725(24)00050-5. [Epub ahead of print] 106559

YAP upregulates AMPKα1 to induce cancer cell senescence.

Yongtong Zhan, Guihao Wu, Xuhong Fan, Ze Fu, Yue Ni, Beini Sun, Hongce Chen, Tongsheng Chen, Xiaoping Wang.

  Yes-associated protein (YAP)-a major effector protein of the Hippo pathway- regulates cell proliferation, differentiation, apoptosis, and senescence. Amp-activated protein kinase (AMPK) is a key sensor that monitors cellular nutrient supply and energy status. Although YAP and AMPK are considered to regulate cellular senescence, it is still unclear whether AMPK is involved in YAP-regulated cellular senescence. Here, we found that YAP promoted AMPKα1 aggregation and localization around mitochondria by co-transfecting CFP-YAP and YFP-AMPKα1 plasmids. Subsequent live cell fluorescence resonance energy transfer (FRET) assay did not exhibit direct interaction between YAP and AMPKα1. FRET, Co-immunoprecipitation, and western blot experiments revealed that YAP directly bound to TEAD, enhancing the expression of AMPKα1 and p-AMPKα. Treatment with verteporfin inhibited YAP's binding to TEAD and reversed the elevated expression of AMPKα1 in the cells overexpressing CFP-YAP. Verteporfin also reduced the proportion of AMPKα1 puncta in the cells co-expressing CFP-YAP and YFP-AMPKα1. In addition, the AMPKα1 puncta were demonstrated to inhibit cell viability, autophagy, and proliferation, and ultimately promote cell senescence. In conclusion, YAP binds to TEAD to upregulate AMPKα1 and promotes the formation of AMPKα1 puncta around mitochondria under the condition of co-expression of CFP-YAP and YFP-AMPKα1, in which AMPKα1 puncta lead to cellular senescence.

Keywords:  AMPKα1; TEAD; YAP; senescence

DOI:  https://doi.org/10.1016/j.biocel.2024.106559
Biochimie. 2024 Mar 15. pii: S0300-9084(24)00066-X. [Epub ahead of print]222 132-150

The molecular crosstalk of the hippo cascade in breast cancer: A potential central susceptibility.

Sulfath Thottungal Parambil, Gisha Rose Antony, Ajeesh Babu Littleflower, Lakshmi Subhadradevi.

  The incidence of breast cancer is perpetually growing globally, and it remains a major public health problem and the leading cause of mortality in women. Though the aberrant activities of the Hippo pathway have been reported to be associated with cancer, constructive knowledge of the pathway connecting the various elements of breast cancer remains to be elucidated. The Hippo transducers, yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ), are reported to be either tumor suppressors, oncogenes, or independent prognostic markers in breast cancer. Thus, there is further need for an explicative evaluation of the dilemma with this molecular contribution of Hippo transducers in modulating breast malignancy. In this review, we summarize the intricate crosstalk of the Hippo pathway in different aspects of breast malignancy, including stem-likeness, cellular signaling, metabolic adaptations, tumor microenvironment, and immune responses. The collective data shows that Hippo transducers play an indispensable role in mammary tumor formation, progression, and dissemination. However, the cellular functions of YAP/TAZ in tumorigenesis might be largely dependent on the mechanical and biophysical cues they interact with, as well as on the cell phenotype. This review provides a glimpse into the plausible biological contributions of the cascade to the inward progression of breast carcinoma and suggests potential therapeutic prospects.

Keywords:  Breast cancer; Hippo signaling; Immune response; Metabolism; Signal transduction; Stemness

DOI:  https://doi.org/10.1016/j.biochi.2024.03.008
Cancer Metastasis Rev. 2024 Mar 22.

Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics.

Bandari BharathwajChetty, Anjana Sajeev, Ravichandran Vishwa, Babu Santha Aswani, Mohammed S Alqahtani, Mohamed Abbas, Ajaikumar B Kunnumakkara.

  Recent advances have brought forth the complex interplay between tumor cell plasticity and its consequential impact on drug resistance and tumor recurrence, both of which are critical determinants of neoplastic progression and therapeutic efficacy. Various forms of tumor cell plasticity, instrumental in facilitating neoplastic cells to develop drug resistance, include epithelial-mesenchymal transition (EMT) alternatively termed epithelial-mesenchymal plasticity, the acquisition of cancer stem cell (CSC) attributes, and transdifferentiation into diverse cell lineages. Nuclear receptors (NRs) are a superfamily of transcription factors (TFs) that play an essential role in regulating a multitude of cellular processes, including cell proliferation, differentiation, and apoptosis. NRs have been implicated to play a critical role in modulating gene expression associated with tumor cell plasticity and drug resistance. This review aims to provide a comprehensive overview of the current understanding of how NRs regulate these key aspects of cancer biology. We discuss the diverse mechanisms through which NRs influence tumor cell plasticity, including EMT, stemness, and metastasis. Further, we explore the intricate relationship between NRs and drug resistance, highlighting the impact of NR signaling on chemotherapy, radiotherapy and targeted therapies. We also discuss the emerging therapeutic strategies targeting NRs to overcome tumor cell plasticity and drug resistance. This review also provides valuable insights into the current clinical trials that involve agonists or antagonists of NRs modulating various aspects of tumor cell plasticity, thereby delineating the potential of NRs as therapeutic targets for improved cancer treatment outcomes.

Keywords:  Cancer; Cancer cell plasticity; Cancer stem cells; Cancer therapy; Chemoresistance; EMT; Nuclear receptors

DOI:  https://doi.org/10.1007/s10555-024-10171-0
Cell Rep. 2024 Mar 15. pii: S2211-1247(24)00225-0. [Epub ahead of print]43(3): 113897

Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance.

Flavio R Palma, Diego R Coelho, Kirthi Pulakanti, Marcelo J Sakiyama, Yunping Huang, Fernando T Ogata, Jeanne M Danes, Alison Meyer, Cristina M Furdui, Douglas R Spitz, Ana P Gomes, Benjamin N Gantner, Sridhar Rao, Vadim Backman, Marcelo G Bonini.

  Chromatin structure is regulated through posttranslational modifications of histone variants that modulate transcription. Although highly homologous, histone variants display unique amino acid sequences associated with specific functions. Abnormal incorporation of histone variants contributes to cancer initiation, therapy resistance, and metastasis. This study reports that, among its biologic functions, histone H3.1 serves as a chromatin redox sensor that is engaged by mitochondrial H2O2. In breast cancer cells, the oxidation of H3.1Cys96 promotes its eviction and replacement by H3.3 in specific promoters. We also report that this process facilitates the opening of silenced chromatin domains and transcriptional activation of epithelial-to-mesenchymal genes associated with cell plasticity. Scavenging nuclear H2O2 or amino acid substitution of H3.1(C96S) suppresses plasticity, restores sensitivity to chemotherapy, and induces remission of metastatic lesions. Hence, it appears that increased levels of H2O2 produced by mitochondria of breast cancer cells directly promote redox-regulated H3.1-dependent chromatin remodeling involved in chemoresistance and metastasis.

Keywords:  CP: Cancer; EMT; H3; ROS; breast cancer; chemoresistance; drug resistance; histone variants; metastasis; redox; thiol oxidation

DOI:  https://doi.org/10.1016/j.celrep.2024.113897
Heliyon. 2024 Mar 15. 10(5): e26850

The p53-mediated cell cycle regulation is a potential mechanism for emodin-suppressing osteosarcoma cells.

Qian Zhang, Shuli Hao, Guangyou Wei, Xiangyu Liu, Yang Miao.

   Background: As the most common primary bone cancer, the therapy of osteosarcoma requires further study. An anthraquinone derivative, emodin, has been found to have anticancer potential. We proposed that emodin suppresses osteosarcoma by cell cycle regulation mediated by p53.
Methods: This study determined the effect of emodin on viability and apoptosis of 6 osteosarcoma cell lines (p53 null cells MG63, G292, and A-673; p53 mutated cells HOS and SK-PN-DW; p53 expressing cells U2OS and 2 osteoblast cell lines), then knockdown p53 in U2OS, and observed the impacts of emodin on p53, p21, cyclin proteins, and cell cycle.
Results: High dose emodin (40-160 μM) induced cell death and apoptosis of all the cell lines; medium dose emodin (20 μM) preferentially inhibited osteosarcoma cells; low dose emodin (1-10 μM) preferentially inhibited p53 expressing osteosarcoma cells. Emodin dose-dependently inhibited p53 and p21 in U2OS. Emodin at 10 μM decreased the expression of Cdk2, E2F, and Cdk1; and increased RB but had no effects on cyclin E and cyclin B. The knockdown of p53 almost eliminated all the impacts of 10 μM emodin on cell cycle proteins.
Conclusions: Emodin suppresses U2OS by p53-mediated cell cycle regulation.

Keywords:  Cell cycle; Emodin; Osteosarcoma; p53

DOI:  https://doi.org/10.1016/j.heliyon.2024.e26850
Nat Commun. 2024 Mar 21. 15(1): 2513

Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma.

Daniel A Ang, Jean-Michel Carter, Kamalakshi Deka, Joel H L Tan, Jianbiao Zhou, Qingfeng Chen, Wee Joo Chng, Nathan Harmston, Yinghui Li.

In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.

DOI: https://doi.org/10.1038/s41467-024-46728-4
Cancer Commun (Lond). 2024 Mar 21.

N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer.

Jiayao Wang, Jiehao Zhang, Hao Liu, Lingnan Meng, Xianchun Gao, Yihan Zhao, Chen Wang, Xiaoliang Gao, Ahui Fan, Tianyu Cao, Daiming Fan, Xiaodi Zhao, Yuanyuan Lu.

   BACKGROUND: Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance.
METHODS: The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry.
RESULTS: Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders.
CONCLUSION: Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β-catenin pathway and exacerbate chemoresistance in GC.

Keywords:  NEAT1; chemoresistance; gastric cancer; hnRNPA2B1; stemness

DOI:  https://doi.org/10.1002/cac2.12534
Noncoding RNA Res. 2024 Jun;9(2): 560-582

Non-coding RNA transcripts, incredible modulators of cisplatin chemo-resistance in bladder cancer through operating a broad spectrum of cellular processes and signaling mechanism.

Mehrdad Hashem, Elaheh Mohandesi Khosroshahi, Melika Aliahmady, Morvarid Ghanei, Yasamin Soofi Rezaie, Yasamin Alsadat Jafari, Fatemeh Rezaei, Ramtin Khodaparast Eskadehi, Kimia Kia Kojoori, Faranak Jamshidian, Noushin Nabavi, Mohsen Rashidi, Farzaneh Hasani Sadi, Afshin Taheriazam, Maliheh Entezari.

  Bladder cancer (BC) is a highly frequent neoplasm in correlation with significant rate of morbidity, mortality, and cost. The onset of BC is predominantly triggered by environmental and/or occupational exposures to carcinogens, such as tobacco. There are two distinct pathways by which BC can be developed, including non-muscle-invasive papillary tumors (NMIBC) and non-papillary (or solid) muscle-invasive tumors (MIBC). The Cancer Genome Atlas project has further recognized key genetic drivers of MIBC along with its subtypes with particular properties and therapeutic responses; nonetheless, NMIBC is the predominant BC presentation among the suffering individuals. Radical cystoprostatectomy, radiotherapy, and chemotherapy have been verified to be the common therapeutic interventions in metastatic tumors, among which chemotherapeutics are more conventionally utilized. Although multiple chemo drugs have been broadly administered for BC treatment, cisplatin is reportedly the most effective chemo drug against the corresponding malignancy. Notwithstanding, tumor recurrence is usually occurred following the consumption of cisplatin regimens, particularly due to the progression of chemo-resistant trait. In this framework, non-coding RNAs (ncRNAs), as abundant RNA transcripts arise from the human genome, are introduced to serve as crucial contributors to tumor expansion and cisplatin chemo-resistance in bladder neoplasm. In the current review, we first investigated the best-known ncRNAs, i.e. microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), correlated with cisplatin chemo-resistance in BC cells and tissues. We noticed that these ncRNAs could mediate the BC-related cisplatin-resistant phenotype through diverse cellular processes and signaling mechanisms, reviewed here. Eventually, diagnostic and prognostic potential of ncRNAs, as well as their therapeutic capabilities were highlighted in regard to BC management.

Keywords:  Cisplatin; Drug resistance; Non-coding RNAs; Signal transduction; Urinary bladder neoplasms

DOI:  https://doi.org/10.1016/j.ncrna.2024.01.009