CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.

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MYC protein stability is negatively regulated by BRD4

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1919507117 ◽

2020 ◽

Vol 117 (24) ◽

pp. 13457-13467 ◽

Cited By ~ 4

Author(s):

Ballachanda N. Devaiah ◽

Jie Mu ◽

Ben Akman ◽

Sheetal Uppal ◽

Jocelyn D. Weissman ◽

...

Keyword(s):

Protein Stability ◽

Chromatin Remodeling ◽

Normal Cell ◽

Target Genes ◽

Kinase Activity ◽

Histone Acetyltransferase ◽

Cell Function ◽

Cellular Processes ◽

Epigenetic Regulator

The protooncogene MYC regulates a variety of cellular processes, including proliferation and metabolism. Maintaining MYC at homeostatic levels is critical to normal cell function; overexpression drives many cancers. MYC stability is regulated through phosphorylation: phosphorylation at Thr58 signals degradation while Ser62 phosphorylation leads to its stabilization and functional activation. The bromodomain protein 4 (BRD4) is a transcriptional and epigenetic regulator with intrinsic kinase and histone acetyltransferase (HAT) activities that activates transcription of key protooncogenes, includingMYC. We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. Importantly, BRD4 degradation, but not inhibition, results in increased levels of MYC protein. Conversely, MYC inhibits BRD4’s HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus. The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. These findings demonstrate that BRD4 negatively regulates MYC levels, which is counteracted by ERK1 activation.

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Diversity roles of CHD1L in normal cell function and tumorigenesis

Biomarker Research ◽

10.1186/s40364-021-00269-w ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Xifeng Xiong ◽

Xudong Lai ◽

Aiguo Li ◽

Zhihe Liu ◽

Ningfang Ma

Keyword(s):

Molecular Basis ◽

Normal Cell ◽

Molecular Mechanisms ◽

Cell Function ◽

Dna Binding Protein ◽

Multifunctional Protein ◽

Structure Characteristics ◽

Cellular Processes ◽

Basic Biology

AbstractChromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a multifunctional protein participated in diverse cellular processes, including chromosome remodeling, cell differentiation and development. CHD1L is a regulator of chromosomal integrity maintenance, DNA repair and transcriptional regulation through its bindings to DNA. By regulating kinds of complex networks, CHD1L has been identified as a potent anti-apoptotic and pro-proliferative factor. CHD1L is also an oncoprotein since its overexpression leads to dysregulation of related downstream targets in various cancers. The latest advances in the functional molecular basis of CHD1L in normal cells will be described in this review. As the same time, we will describe the current understanding of CHD1L in terms of structure, characteristics, function and the molecular mechanisms underlying CHD1L in tumorigenesis. We inference that the role of CHD1L which involve in multiple cellular processes and oncogenesis is well worth further studying in basic biology and clinical relevance.

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ER-to-Golgi trafficking of procollagen in the absence of large carriers

10.1101/339804 ◽

2018 ◽

Author(s):

Janine McCaughey ◽

Nicola L. Stevenson ◽

Stephen Cross ◽

David J. Stephens

Keyword(s):

Extracellular Matrix ◽

Endoplasmic Reticulum ◽

Normal Cell ◽

Cell Function ◽

Collagen Matrix ◽

Type I ◽

Loop Model ◽

Type I Procollagen ◽

Short Loop ◽

Insight Into

AbstractSecretion and assembly of collagen is fundamental to the function of the extracellular matrix. Defects in the assembly of a collagen matrix lead to pathologies including fibrosis and osteogenesis imperfecta. Owing to the size of fibril-forming procollagen molecules it is assumed that they are transported from the endoplasmic reticulum to the Golgi in specialised large COPII-dependent carriers. Here, analysing endogenous procollagen and a new engineered GFP-tagged form, we show that transport to the Golgi occurs in the absence of large carriers. Large GFP-positive structures are observed occasionally but these are non-dynamic, are not COPII-positive, and label with markers of the ER. We propose a “short-loop” model of COPII-dependent ER-to-Golgi traffic that, while consistent with models of ERGIC-dependent expansion of COPII carriers, does not invoke long-range trafficking of large vesicular structures. Our findings provide an important insight into the process of procollagen trafficking and reveal a short-loop pathway from the ER to the Golgi, without the use of large carriers.SummaryTrafficking of procollagen is essential for normal cell function. Here, imaging of GFP-tagged type I procollagen reveals that it is transported from the endoplasmic reticulum to the Golgi, without the use of large carriers.

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PTEN loss correlates with T cell exclusion across human cancers

BMC Cancer ◽

10.1186/s12885-021-08114-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ziying Lin ◽

Lixia Huang ◽

Shao Li Li ◽

Jincui Gu ◽

Xiaoxian Cui ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Helper Cells ◽

Pi3k Pathway ◽

T Helper ◽

Immune Microenvironment ◽

Pten Loss ◽

Pathway Activation ◽

Tumor Types ◽

T Cell Exclusion

Abstract Background Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. Methods Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. Results We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. Conclusion These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.

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A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function

Communications Biology ◽

10.1038/s42003-020-01565-1 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Jeremy To ◽

Doug Quackenbush ◽

Emily Rowell ◽

Lilin Li ◽

Connor Reed ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

Cell Activity ◽

Cytotoxic T Cell ◽

Dependent Manner ◽

Cyclin Dependent Kinase ◽

Histocompatibility Complex ◽

T Cell Function ◽

Cytolytic Granule ◽

Screening Platform

AbstractOvercoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8+ T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents.

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Considerations when investigating lncRNA function in vivo

eLife ◽

10.7554/elife.03058 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 222

Author(s):

Andrew R Bassett ◽

Asifa Akhtar ◽

Denise P Barlow ◽

Adrian P Bird ◽

Neil Brockdorff ◽

...

Keyword(s):

Normal Cell ◽

Regulatory Elements ◽

Genomic Locus ◽

Cellular Processes ◽

Cell Processes ◽

Non Coding Rnas ◽

Per Se ◽

Dna Regulatory Elements

Although a small number of the vast array of animal long non-coding RNAs (lncRNAs) have known effects on cellular processes examined in vitro, the extent of their contributions to normal cell processes throughout development, differentiation and disease for the most part remains less clear. Phenotypes arising from deletion of an entire genomic locus cannot be unequivocally attributed either to the loss of the lncRNA per se or to the associated loss of other overlapping DNA regulatory elements. The distinction between cis- or trans-effects is also often problematic. We discuss the advantages and challenges associated with the current techniques for studying the in vivo function of lncRNAs in the light of different models of lncRNA molecular mechanism, and reflect on the design of experiments to mutate lncRNA loci. These considerations should assist in the further investigation of these transcriptional products of the genome.

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The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer

Biomedicines ◽

10.3390/biomedicines9080921 ◽

2021 ◽

Vol 9 (8) ◽

pp. 921

Author(s):

Ekaterina Mikhailovna Stasevich ◽

Matvey Mikhailovich Murashko ◽

Lyudmila Sergeevna Zinevich ◽

Denis Eriksonovich Demin ◽

Anton Markovich Schwartz

Keyword(s):

Malignant Tumors ◽

Current Data ◽

Cellular Processes ◽

Cell Divisions ◽

Specific Tumor ◽

Different Types ◽

Myc Gene ◽

Non Coding Rnas ◽

Tumor Types

Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.

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PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells

International Journal of Cell Biology ◽

10.1155/2010/207420 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Nilsa Rivera-Del Valle ◽

Shan Gao ◽

Claudia P. Miller ◽

Joy Fulbright ◽

Carolina Gonzales ◽

...

Keyword(s):

Hdac Inhibitor ◽

Hydroxamic Acid ◽

Histone Deacetylase Inhibitors ◽

Leukemia Cells ◽

Ros Generation ◽

Caspase 8 ◽

Death Domain ◽

Apoptosis Induction ◽

Tumor Types ◽

Insight Into

Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels.

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Specific Modification of Aged Proteasomes Revealed by Tag-Exchangeable Knock-In Mice

Molecular and Cellular Biology ◽

10.1128/mcb.00426-18 ◽

2018 ◽

Vol 39 (1) ◽

Cited By ~ 10

Author(s):

Takuya Tomita ◽

Shoshiro Hirayama ◽

Yasuyuki Sakurai ◽

Yuki Ohte ◽

Hidehito Yoshihara ◽

...

Keyword(s):

Cell Function ◽

Fluorescent Protein ◽

Embryonic Fibroblasts ◽

Α Subunit ◽

Biochemical Alterations ◽

Cellular Processes ◽

Responsible Gene ◽

Intracellular Protein Degradation ◽

Green Fluorescent

ABSTRACT The proteasome is the proteolytic machinery at the center of regulated intracellular protein degradation and participates in various cellular processes. Maintaining the quality of the proteasome is therefore important for proper cell function. It is unclear, however, how proteasomes change over time and how aged proteasomes are disposed. Here, we show that the proteasome undergoes specific biochemical alterations as it ages. We generated Rpn11-Flag/enhanced green fluorescent protein (EGFP) tag-exchangeable knock-in mice and established a method for selective purification of old proteasomes in terms of their molecular age at the time after synthesis. The half-life of proteasomes in mouse embryonic fibroblasts isolated from these knock-in mice was about 16 h. Using this tool, we found increased association of Txnl1, Usp14, and actin with the proteasome and specific phosphorylation of Rpn3 at Ser 6 in 3-day-old proteasomes. We also identified CSNK2A2 encoding the catalytic α′ subunit of casein kinase II (CK2α′) as a responsible gene that regulates the phosphorylation and turnover of old proteasomes. These findings will provide a basis for understanding the mechanism of molecular aging of the proteasome.

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Mechanistic insight into the ruthenium-catalysed anti-Markovnikov hydration of alkynes using a self-assembled complex: a crucial role for ligand-assisted proton shuttle processes

Dalton Transactions ◽

10.1039/c4dt00712c ◽

2014 ◽

Vol 43 (29) ◽

pp. 11277-11285 ◽

Cited By ~ 25

Author(s):

Bernhard Breit ◽

Urs Gellrich ◽

Timothy Li ◽

Jason M. Lynam ◽

Lucy M. Milner ◽

...

Keyword(s):

Experimental Study ◽

Crucial Role ◽

Ligand Complex ◽

Mechanistic Insight ◽

Self Assembled ◽

Insight Into

A combined computational and experimental study into the mechanism of the anti-Markovnikov hydration of phenylacetylene by a self-assembled ligand complex.

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