Targeting the MYC Ubiquitination-Proteasome Degradation Pathway for Cancer Therapy

Deregulated MYC overexpression and activation contributes to tumor growth and progression. Given the short half-life and unstable nature of the MYC protein, it is not surprising that the oncoprotein is highly regulated via diverse posttranslational mechanisms. Among them, ubiquitination dynamically controls the levels and activity of MYC during normal cell growth and homeostasis, whereas the disturbance of the ubiquitination/deubiquitination balance enables unwanted MYC stabilization and activation. In addition, MYC is also regulated by SUMOylation which crosstalks with the ubiquitination pathway and controls MYC protein stability and activity. In this mini-review, we will summarize current updates regarding MYC ubiquitination and provide perspectives about these MYC regulators as potential therapeutic targets in cancer.

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GENE-39. CRISPRi-BASED RADIATION MODIFIER SCREEN IDENTIFIES LONG NON-CODING RNA THERAPEUTIC TARGETS IN GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.441 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi106-vi106

Author(s):

S John Liu ◽

Martina Malatesta ◽

Kyounghee Seo ◽

Brian Lien ◽

Sung Hong ◽

...

Keyword(s):

Cancer Therapy ◽

Tumor Growth ◽

Therapeutic Targets ◽

Standard Of Care ◽

Cell Types ◽

Normal Brain ◽

Current Standard ◽

Specific Expression ◽

Pediatric Glioma ◽

And Function

Abstract Long noncoding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer therapy. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients. Here, we used a CRISPR interference (CRISPRi) platform to systematically screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modified cell growth in the presence of clinically relevant doses of fractionated radiation. 34 of these lncRNA hits sensitized cells to radiation, and based on their expression in adult and pediatric glioma, nine of these hits were prioritized as lncRNA Glioma Radiation Sensitizers (lncGRS). Knockdown of lncGRS-1 – a primate-conserved, nuclear-enriched lncRNA – inhibited the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a 3-dimensional tissue substrate to model the invasive growth of glioma, we found that antisense oligonucleotides (ASOs) targeting lncGRS-1 selectively decreased tumor growth synergistically with radiation therapy. These studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome that can enhance the standard-of-care for cancer therapy.

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Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy

Pharmaceuticals ◽

10.3390/ph14101053 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1053

Author(s):

Dong-Hee Lee ◽

Seunghyun Choi ◽

Yoon Park ◽

Hyung-seung Jin

Keyword(s):

Cell Growth ◽

Cancer Therapy ◽

Immune Evasion ◽

Human Cancer ◽

Therapeutic Targets ◽

Structural Features ◽

Metabolic Reprogramming ◽

Cancer Development ◽

Hallmarks Of Cancer ◽

Mucus Barrier

The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.

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Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

Nuklearmedizin ◽

10.1055/s-0037-1620623 ◽

1977 ◽

Vol 16 (04) ◽

pp. 157-162 ◽

Cited By ~ 1

Author(s):

C. Schümichen ◽

B. Mackenbrock ◽

G. Hoffmann

Keyword(s):

Normal Saline ◽

Half Life ◽

Compound A ◽

Short Half Life ◽

Low Concentrations ◽

The Stability ◽

Kinetics Of ◽

In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

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Faculty Opinions recommendation of IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.722032138.793500843 ◽

2014 ◽

Author(s):

James Beeson

Keyword(s):

Plasmodium Falciparum ◽

Half Life ◽

Antibody Responses ◽

Igg Antibody ◽

Short Half Life ◽

Merozoite Antigens

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Faculty Opinions recommendation of Resolvins suppress tumor growth and enhance cancer therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732206946.793541364 ◽

2018 ◽

Author(s):

Alberto Mantovani

Keyword(s):

Cancer Therapy ◽

Tumor Growth

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Faculty Opinions recommendation of Resolvins suppress tumor growth and enhance cancer therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732206946.793540814 ◽

2017 ◽

Author(s):

David Potter

Keyword(s):

Cancer Therapy ◽

Tumor Growth

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Regulation of A Kinase Cascade Involved in Cancer and Normal Cell Growth.

10.21236/ada349593 ◽

1997 ◽

Author(s):

Dennis J. Templeton

Keyword(s):

Cell Growth ◽

Normal Cell ◽

Kinase Cascade

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Inhibited MicroRNA-301 Restrains Angiogenesis and Cell Growth in Esophageal Squamous Cell Carcinoma by Elevating PTEN

Nanoscale Research Letters ◽

10.1186/s11671-020-03452-4 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Bin Wang ◽

Peiyan Hua ◽

Ruimin Wang ◽

Jindong Li ◽

Guangxin Zhang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Growth ◽

Esophageal Squamous Cell Carcinoma ◽

Tumor Growth ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cell Cycle Distribution ◽

Pten Inhibition ◽

The Impact

Abstract Objective Esophageal squamous cell carcinoma (ESCC) is featured by early metastasis and late diagnosis. MicroRNA-301 (miR-301) is known to participate in diverse cancers. Nevertheless, effects of miR-301 on ESCC remain unexplored. Thus, we aim to explore the role of miR-301 in ESCC progression. Methods Expression of miR-301 and phosphatase and tensin homologue (PTEN) in ESCC tissues and cell lines was assessed. Next, the screened cells were treated with altered miR-301 or PTEN oligonucleotide and plasmid, and then, the colony formation ability, cell viability, migration, invasion, cell cycle distribution and apoptosis of ESCC cells were assessed. Moreover, tumor growth and microvessel density (MVD) were also assessed, and the targeting relationship between miR-301 and PTEN was affirmed. Results MiR-301 was upregulated, and PTEN was downregulated in ESCC tissues and cells. KYSE30 cells and Eca109 cells were selected for functional assays. In KYSE30 cells, inhibited miR-301 or overexpressed PTEN suppressed cell malignant behaviors, and silenced PTEN eliminated the impact of miR-301 inhibition on ESCC progression. In Eca109 cells, miR-301 overexpression or PTEN inhibition promoted cell malignant behaviors, and PTEN overexpression reversed the effects of miR-301 elevation on ESCC progression. The in vivo assay revealed that miR-301 inhibition or PTEN overexpression repressed ESCC tumor growth and MVD, and miR-301 elevation or PTEN reduction had contrary effects. Moreover, PTEN was targeted by miR-301. Conclusion Taken together, results in our study revealed that miR-301 affected cell growth, metastasis and angiogenesis via regulating PTEN expression in ESCC.

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Oligoribonuclease is the primary degradative enzyme for pGpG inPseudomonas aeruginosathat is required for cyclic-di-GMP turnover

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1507245112 ◽

2015 ◽

Vol 112 (36) ◽

pp. E5048-E5057 ◽

Cited By ~ 75

Author(s):

Mona W. Orr ◽

Gregory P. Donaldson ◽

Geoffrey B. Severin ◽

Jingxin Wang ◽

Herman O. Sintim ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Active Site ◽

Half Life ◽

Biofilm Formation ◽

Degradation Pathway ◽

Dependent Manner ◽

Capillary Action ◽

Diguanylate Cyclases ◽

Active Site Mutants ◽

Degradative Enzyme

The bacterial second messenger cyclic di-GMP (c-di-GMP) controls biofilm formation and other phenotypes relevant to pathogenesis. Cyclic-di-GMP is synthesized by diguanylate cyclases (DGCs). Phosphodiesterases (PDE-As) end signaling by linearizing c-di-GMP to 5ʹ-phosphoguanylyl-(3ʹ,5ʹ)-guanosine (pGpG), which is then hydrolyzed to two GMP molecules by yet unidentified enzymes termed PDE-Bs. We show that pGpG inhibits a PDE-A fromPseudomonas aeruginosa. In a dual DGC and PDE-A reaction, excess pGpG extends the half-life of c-di-GMP, indicating that removal of pGpG is critical for c-di-GMP homeostasis. Thus, we sought to identify the PDE-B enzyme(s) responsible for pGpG degradation. A differential radial capillary action of ligand assay-based screen for pGpG binding proteins identified oligoribonuclease (Orn), an exoribonuclease that hydrolyzes two- to five-nucleotide-long RNAs. Purified Orn rapidly converts pGpG into GMP. To determine whether Orn is the primary enzyme responsible for degrading pGpG, we assayed cell lysates of WT and ∆ornstrains ofP. aeruginosaPA14 for pGpG stability. The lysates from ∆ornshowed 25-fold decrease in pGpG hydrolysis. Complementation with WT, but not active site mutants, restored hydrolysis. Accumulation of pGpG in the ∆ornstrain could inhibit PDE-As, increasing c-di-GMP concentration. In support, we observed increased transcription from the c-di-GMP–regulatedpelpromoter. Additionally, the c-di-GMP–governed auto-aggregation and biofilm phenotypes were elevated in the ∆ornstrain in apel-dependent manner. Finally, we directly detect elevated pGpG and c-di-GMP in the ∆ornstrain. Thus, we identified that Orn serves as the primary PDE-B enzyme that removes pGpG, which is necessary to complete the final step in the c-di-GMP degradation pathway.

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