bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒02‒26
six papers selected by
Ankita Daiya, Birla Institute of Technology and Science



  1. Biomedicines. 2023 Feb 20. pii: 633. [Epub ahead of print]11(2):
      Prostate cancer (PC) is a common malignancy and is one of the leading causes of cancer-related death in men worldwide. Osteosarcoma (OS) is the most common bone cancer, representing 20-40% of all bone malignancy cases. Cancer metastasis is a process by which malignant tumor cells detach from the primary tumor site via a cascade of processes and migrate to secondary sites through the blood circulation or lymphatic system to colonize and form secondary tumors. PC has a specific affinity to the bone based on the "seed and soil" theory; once PC reach the bone, it becomes incurable. Several studies have identified long noncoding RNAs (lncRNAs) as potential targets for cancer therapy or as diagnostic and prognostic biomarkers. The dysregulation of various lncRNAs has been found in various cancer types, including PC, OS, and metastasis. However, the mechanisms underlying lncRNA oncogenic activity in tumor progression and metastasis are extremely complex and remain incompletely understood. Therefore, understanding oncogenic lncRNAs and their role in OS, PC, and metastasis and the underlying mechanism may help better manage and treat this malignancy. The aim of this review is to summarize current knowledge of oncogenic lncRNAs and their involvement in PC, OS, and bone metastasis.
    Keywords:  lncRNAs; metastasis; osteosarcoma; prostate cancer
    DOI:  https://doi.org/10.3390/biomedicines11020633
  2. EBioMedicine. 2023 Feb 22. pii: S2352-3964(23)00048-8. [Epub ahead of print]89 104483
      Drug-tolerant persister (DTP) cells have attracted significant interest, given their predominant role in treatment failure. In this respect, DTP cells reportedly survive after anticancer drug exposure, and their DNA repair mechanisms are altered to enhance adaptive mutation, accounting for the emergence of drug-resistant mutations. DTP cells resume proliferation upon treatment withdrawal and are responsible for cancer relapse. Current evidence suggests that DTP cells mediate redox signaling-mediated cellular homeostasis by developing various adaptive mechanisms, especially metabolic reprogramming that promotes mitochondrial oxidative respiration and a robust antioxidant process. There is an increasing consensus that disrupting redox homeostasis by intervening with redox signaling is theoretically a promising therapeutic strategy for targeting these sinister cells. In this review, we provide a comprehensive overview of the characteristics of DTP cells and the underlying mechanisms involved in redox signaling, aiming to provide a unique perspective on potential therapeutic applications based on their vulnerabilities to redox regulation.
    Keywords:  Cancer relapse; Drug resistance; Drug-tolerant persister; Redox homeostasis; Redox signaling
    DOI:  https://doi.org/10.1016/j.ebiom.2023.104483
  3. Lab Invest. 2023 Jan 10. pii: S0023-6837(22)03991-5. [Epub ahead of print]103(5): 100053
      Gliomas are the most common and lethal primary brain tumors in adults. Glioblastomas, the most frequent and aggressive form of gliomas, represent a therapeutic challenge as no curative treatment exists to date, and the prognosis remains extremely poor. Recently, the transcriptional cofactors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) belonging to the Hippo pathway have emerged as a major determinant of malignancy in solid tumors, including gliomas. However, the mechanisms involved in its regulation, particularly in brain tumors, remain ill-defined. In glioblastomas, EGFR represents one of the most altered oncogenes affected by chromosomal rearrangements, mutations, amplifications, and overexpression. In this study, we investigated the potential link between epidermal growth factor receptor (EGFR) and the transcriptional cofactors YAP and TAZ by in situ and in vitro approaches. We first studied their activation on tissue microarray, including 137 patients from different glioma molecular subtypes. We observed that YAP and TAZ nuclear location was highly associated with isocitrate dehydrogenase 1/2 (IDH1/2) wild-type glioblastomas and poor patient outcomes. Interestingly, we found an association between EGFR activation and YAP nuclear location in glioblastoma clinical samples, suggesting a link between these 2 markers contrary to its ortholog TAZ. We tested this hypothesis in patient-derived glioblastoma cultures by pharmacologic inhibition of EGFR using gefinitib. We showed an increase of S397-YAP phosphorylation associated with decreased AKT phosphorylation after EGFR inhibition in phosphatase and tensin homolog (PTEN) wild-type cultures, unlike PTEN-mutated cell lines. Finally, we used bpV(HOpic), a potent PTEN inhibitor, to mimic the effect of PTEN mutations. We found that the inhibition of PTEN was sufficient to revert back the effect induced by Gefitinib in PTEN-wild-type cultures. Altogether, to our knowledge, these results show for the first time the regulation of pS397-YAP by the EGFR-AKT axis in a PTEN-dependent manner.
    Keywords:  AKT; EGFR; PTEN; TAZ; YAP; glioblastomas
    DOI:  https://doi.org/10.1016/j.labinv.2022.100053
  4. Biomolecules. 2023 Feb 20. pii: 398. [Epub ahead of print]13(2):
      The epithelial to mesenchymal transition (EMT) is a cellular process that has been linked to the promotion of aggressive cellular features in many cancer types. It is characterized by the loss of the epithelial cell phenotype and a shift to a more mesenchymal phenotype and is accompanied by an associated change in cell markers. EMT is highly complex and regulated via multiple signaling pathways. While the importance of EMT is classically described for carcinomas-cancers of epithelial origin-it has also been clearly demonstrated in non-epithelial cancers, including osteosarcoma (OS), a primary bone cancer predominantly affecting children and young adults. Recent studies examining EMT in OS have highlighted regulatory roles for multiple proteins, non-coding nucleic acids, and components of the tumor micro-environment. This review serves to summarize these experimental findings, identify key families of regulatory molecules, and identify potential therapeutic targets specific to the EMT process in OS.
    Keywords:  cancer therapeutics; circular RNAs; epithelial-mesenchymal transition; long non-coding RNAs; microRNAs; osteosarcoma; transcriptional regulation; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom13020398
  5. FEBS Open Bio. 2023 Feb 21.
      The most common type of kidney cancer in adults is renal cell carcinoma (RCC), which accounts for approximately 90% of cases. RCC is a variant disease with numerous subtypes; the most common subtype is clear cell RCC (ccRCC, 75%), followed by papillary RCC (pRCC, 10%) and chromogenic RCC (chRCC, 5%). To identify a genetic target for all subtypes, we analyzed The Cancer Genome Atlas (TCGA) databases of clear cell RCC, papillary RCC, and chromophobe RCC. Enhancer of zeste homolog 2 (EZH2), which encodes a methyltransferase, was observed to be significantly upregulated in tumors. The EZH2 inhibitor tazemetostat induced anti-cancer effects in RCC cells. TCGA analysis revealed that large tumor suppressor kinase 1 (LATS1), a key tumor suppressor of the Hippo pathway, was significantly downregulated in tumors; expression of LATS1 was increased by tazemetostat. Through additional experiments, we confirmed that LATS1 plays a crucial role in EZH2 inhibition, and has a negative association with EZH2. Therefore, we suggest that epigenetic control could be a novel therapeutic strategy for three subtypes of RCC.
    Keywords:  EZH2; Hippo-pathway; LATS1; Renal cell carcinoma; tazemetostat
    DOI:  https://doi.org/10.1002/2211-5463.13579
  6. J Orthop Surg Res. 2023 Feb 23. 18(1): 132
      BACKGROUND: Osteosarcoma is a common primary bone malignancy prevalent among adolescents and young adults. PTEN-induced kinase 1 (PINK1) regulates Parkinson's disease, but its role in cancers is unknown.OBJECTIVE: This study was designed to analyze the mechanism by which PINK1 affects osteosarcoma using bioinformatics and cell experiments.
    MATERIALS AND METHODS: The gene expression profiles were downloaded from the TARGET database. Several online databases were used to analyze the expression and protein‒protein interaction networks. CCK-8 cell viability assays and cisplatin treatment were used to assess cell activity with or without cisplatin treatment. Acridine orange/ethidium bromide (AO/EB) fluorescence staining was used to calculate the percentage of apoptotic cells.
    RESULTS: Through bioinformatics analysis, we found that high expression of PINK1 was associated with poor prognosis in patients with osteosarcoma, and PINK1 inhibited apoptosis and promoted proliferation pathways. Next, we found that both PINK1 mRNA and protein levels were upregulated in osteosarcoma tissues. Additionally, we found that PTEN was reduced, while FOXO3a was markedly increased in osteosarcoma, suggesting that FOXO3a and not PTEN induced the overexpression of PINK1. CCK-8 and clonogenic assays showed that the knockdown of PINK1 decreased the growth of U2OS osteosarcoma cells. Ki67 immunofluorescence staining revealed that reduced cell proliferation in U2OS cells resulted in the depletion of PINK1. In addition, our AO/EB staining results indicated that the knockdown of PINK1 resulted in an increase in apoptotic cells and increased the levels of cleaved caspase-3. Furthermore, our experiments revealed that cisplatin promotes OS cell apoptosis by downregulating PINK1.
    CONCLUSION: Collectively, our findings demonstrate that PINK1 is crucially involved in osteosarcoma and suggests that it can promote the apoptosis of OS cells as the downstream target gene of cisplatin.
    Keywords:  Apoptosis; Cisplatin; FOXO3a; Osteosarcoma; PINK1
    DOI:  https://doi.org/10.1186/s13018-023-03615-w