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Related Concept Videos

Histone Modification02:32

Histone Modification

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The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
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The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
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Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
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Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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Inheritance of Chromatin Structures03:17

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Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying...
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Chromatin Modification in iPS Cells01:32

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Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
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HDAC8 Enhances the Function of HIF-2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC.

Kang Qian1,2,3, Wei Li1,2, Shangqing Ren4

  • 1Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 29, 2024
PubMed
Summary
This summary is machine-generated.

Drug resistance in clear cell renal cell carcinoma (ccRCC) to Tyrosine kinase inhibitors (TKIs) is a challenge. This study identifies HDAC8 as a key player in TKI resistance, offering new therapeutic targets for ccRCC treatment.

Keywords:
ETS1HDAC8TKIsccRCC

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Drug resistance to Tyrosine kinase inhibitors (TKIs) limits survival in clear cell renal cell carcinoma (ccRCC).
  • Understanding the mechanisms of acquired resistance is crucial for developing effective ccRCC therapies.

Purpose of the Study:

  • To identify novel targets involved in ccRCC resistance to TKIs.
  • To elucidate the molecular mechanisms underlying HDAC8's role in TKI resistance.
  • To develop strategies to overcome TKI resistance in ccRCC.

Main Methods:

  • Genome-wide CRISPR-based screening to identify resistance-associated genes.
  • Molecular assays to investigate protein interactions and post-translational modifications (acetylation, phosphorylation).
  • Synthesis and evaluation of HDAC8-based Proteolysis Targeting Chimeras (PROTACs).

Main Results:

  • HDAC8 was identified as a key mediator decreasing ccRCC sensitivity to sunitinib.
  • HDAC8 promotes TKI resistance by deacetylating ETS1, enhancing ETS1/HIF-2α complex activity.
  • HDAC8 inhibition upregulates NEK1, which further promotes ETS1/HIF-2α interaction.
  • TKI treatment increases HDAC8 expression via STAT3 inhibition, contributing to acquired resistance.
  • HDAC8-in-PROTACs were synthesized to degrade HDAC8 and overcome TKI resistance.

Conclusions:

  • HDAC8 plays a critical role in acquired resistance to TKIs in ccRCC.
  • Targeting HDAC8, particularly through PROTACs, presents a promising therapeutic strategy for overcoming TKI resistance in ccRCC.
  • HDAC8 is a potential therapeutic candidate for ccRCC-targeted therapies.