Regulator of ribosome synthesis 1 (RRS1) is a key factor in ribosome biosynthesis and other cellular functions. High level of RRS1 in breast cancer cell lines is associated with increased cell proliferation, invasion and migration. RRS1 controls the assembly of the 60s subunit and maturation of 25S rRNA during ribosome biosynthesis.
In this study, lentiviral transfection of sh‑RNA was used to knock down the level of RRS1, to detect the effect of RRS1 on cell function and to explore the specific mechanism of RRS1 affecting cell invasion and metastasis by COIP and dual‑luciferase reporter gene assays.
The present study found that RRS1 knockdown reduced the accumulation of ribosome protein L11 (RPL11) in the nucleolus, which then migrated to the nucleoplasm and bound to c‑Myc. This inhibited trans‑activation of SNAIL by c‑Myc and eventually decreased the invasion and metastasis capacity of the human breast cancer cell line BT549.
Taken together, RRS1 regulates invasion and metastasis of human breast cancer cells through the RPL11‑c‑Myc‑SNAIL axis. The findings are of great significance for exploring the mechanism of breast cancer invasion and metastasis and the corresponding regulatory factors.
Jumonji-C domain-containing protein 5 suppresses proliferation and aerobic glycolysis in pancreatic cancer cells in a c–Myc-dependent manner
Despite the importance of metabolic reprogramming in cancer cells, the molecular mechanism regulating the tumor metabolic shift is still poorly understood. Deregulation of Jumonji-C domain-containing protein 5 (JMJD5) has been associated with multiple facets of biological processes in cancer cells.
However, the role of JMJD5 in pancreatic cancer cells has seldom been discussed and requires further investigation. In the present study, by silencing or overexpressing JMJD5 in pancreatic cancer cells, we examined the impact of JMJD5 on cell proliferation and glucose metabolism. Using a dual luciferase assay, we assessed the effect of JMJD5 on the transcriptional activity of the c-Myc target gene.
Analyzing The Cancer Genome Atlas and the Gene Expression Omnibus datasets revealed that low JMJD5 expression was associated with poor prognosis in patients with pancreatic cancer.
JMJD5 loss promoted pancreatic cancer cell proliferation and induced a cellular metabolic shift from oxidative phosphorylation to glycolysis. In addition, in vivo experiments confirmed that ectopic JMJD5 expression inhibited cancer cell growth and the expression of glycolytic enzymes, such as lactate dehydrogenase and phosphoglycerate kinase 1.
Moreover, JMJD5 negatively regulated c-Myc expression, the main regulator of cancer metabolism, leading to decreased c-Myc-targeted gene expression. Overall, the present study indicated that decreased JMJD5 expression promoted cell proliferation and glycolytic metabolism in pancreatic cancer cells in a c-Myc-dependent manner.
Imaging-Based Screening of Deubiquitinating Proteases Identifies Otubain-1 as a Stabilizer of c–MYC
The ubiquitin-proteasome pathway precisely controls the turnover of transcription factors in the nucleus, playing an important role in maintaining appropriate quantities of these regulatory proteins. The transcription factor c-MYC is essential for normal development and is a critical cancer driver. Despite being highly expressed in several tissues and malignancies, the c-MYC protein is also continuously targeted by the ubiquitin-proteasome pathway, which can either facilitate or inhibit c-MYC degradation. Deubiquitinating proteases can remove ubiquitin chains from target proteins and rescue them from proteasomal digestion.
This study sought to determine novel elements of the ubiquitin-proteasome pathway that regulate c-MYC levels. We performed an overexpression screen with 41 human proteases to identify which deubiquitinases stabilize c-MYC. We discovered that the highly expressed Otubain-1 (OTUB1) protease increases c-MYC protein levels.
Confirming its role in enhancing c-MYC activity, we found that elevated OTUB1 correlates with inferior clinical outcomes in the c-MYC-dependent cancer multiple myeloma, and overexpression of OTUB1 accelerates the growth of myeloma cells. In summary, our study identifies OTUB1 as a novel amplifier of the proto-oncogene c-MYC.
Rational design of small-molecules to recognize G-quadruplexes of c–MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer
DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging.
We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity.
The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures.
The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures.
Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.
c–Myc Targets HDAC3 to Suppress NKG2DL Expression and Innate Immune Response in N-Type SCLC through Histone Deacetylation
SCLC is an aggressive malignancy with a very poor prognosis and limited effective therapeutic options. Despite the high tumor mutational burden, responses to immunotherapy are rare in SCLC patients, which may be due to the lack of immune surveillance.
Here, we aimed to examine the role and mechanism of oncogene MYC in the regulation of NKG2DL, the most relevant NK-activating ligand in SCLC-N.
Western Blotting, Immunofluorescence, flow cytometry, quantitative real-time PCR (qRT-PCR), Co-Immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and Cytotoxicity assay were used on H2227 cells, H446 cells, and other SCLC cell lines, and we found that c-Myc negatively regulated NKG2DL expression in SCLC-N cells. Mechanistically, c-Myc recruited HDAC3 to deacetylate H3K9ac at the promoter regions of MICA and MICB, suppressing the MICA/B expression of SCLC-N cells and the cytotoxicity of NK cells.
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Treatment with selective HDAC3 inhibitor up-regulated the expression of NKG2DL on SCLC-N cells and increased the cytotoxicity of NK cells. Furthermore, analysis of the CCLE and Kaplan-Meier plotter data performed the negative correlation between MYC and NKG2DL in SCLC-N cells and the correlation with the prognosis of lung cancer patients.
Collectively, the results provided the new insight into the role and mechanism of c-Myc/HDAC3 axis in NKG2DL expression and innate immune escape of SCLC-N, suggesting the potential target for SCLC-N immunotherapy.
