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Last update 08 May 2025

HDAC3 x SIAH2

Last update 08 May 2025

Basic Info

Related Targets

HDAC3SIAH2

Drugs associated with HDAC3 x SIAH2

COOTO-Me

Target

HDAC3 x SIAH2

Mechanism

HDAC3 inhibitors [+1]

Active Org.

Icahn School of Medicine at Mount Sinai [+1]

Originator Org.

Shenyang Pharmaceutical University [+1]

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HDAC3 x SIAH2

100 Translational Medicine associated with HDAC3 x SIAH2

0 Patents (Medical) associated with HDAC3 x SIAH2

Literatures (Medical) associated with HDAC3 x SIAH2

27 Dec 2022·Cancer Research Communications

Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation

Article

Author: Maneix, Laure ; Mistry, Ragini M. ; Lulla, Premal ; Moree, Shannon E. ; Stossi, Fabio ; Iakova, Polina ; Catic, André ; Sahin, Ergun ; Sun, Zheng ; Yellapragada, Sarvari V. ; Hsu, Joanne I.

Proteasome inhibitors have become the standard of care for multiple myeloma. Blocking protein degradation particularly perturbs the homeostasis of short-lived polypeptides such as transcription factors and epigenetic regulators. To determine how proteasome inhibitors directly impact gene regulation, we performed an integrative genomics study in multiple myeloma cells. We discovered that proteasome inhibitors reduce the turnover of DNA-associated proteins and repress genes necessary for proliferation through epigenetic silencing. Specifically, proteasome inhibition results in the localized accumulation of histone deacetylase 3 (HDAC3) at defined genomic sites, which reduces H3K27 acetylation and increases chromatin condensation. The loss of active chromatin at super-enhancers critical for multiple myeloma, including the super-enhancer controlling the proto-oncogene c-MYC, reduces metabolic activity and cancer cell growth. Epigenetic silencing is attenuated by HDAC3 depletion, suggesting a tumor-suppressive element of this deacetylase in the context of proteasome inhibition. In the absence of treatment, HDAC3 is continuously removed from DNA by the ubiquitin ligase Seven in Absentia Homolog 2 (SIAH2). Overexpression of SIAH2 increases H3K27 acetylation at c-MYC–controlled genes, increases metabolic output, and accelerates cancer cell proliferation. Our studies indicate a novel therapeutic function of proteasome inhibitors in multiple myeloma by reshaping the epigenetic landscape in an HDAC3-dependent manner. As a result, blocking the proteasome effectively antagonizes c-MYC and the genes controlled by this proto-oncogene.Significance:Integrative genomics reveals that a key function of proteasome inhibitors involves limiting the activity of MYC and MYC-dependent genes through epigenetic repression.

01 Jun 2015·Molecules and CellsQ3 · BIOLOGY

miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3

Q3 · BIOLOGY

Article

Author: Park, Deokbum ; Kim, Hyuna ; Jeoung, Dooil ; Kim, Youngmi

We previously reported the role of histone deacetylase 3 (HDAC3) in response to anti-cancer drugs. The decreased expression of HDAC3 in anti-cancer drug-resistant cancer cell line is responsible for the resistance to anti-cancer drugs. In this study, we investigated molecular mechanisms associated with regulation of HDAC3 expression. MG132, an inhibitor of proteasomal degradation, induced the expression of HDAC3 in various anti-cancer drug-resistant cancer cell lines. Ubiquitination of HDAC3 was observed in various anti-cancer drug-resistant cancer cell lines. HDAC3 showed an interaction with SIAH2, an ubiquitin E3 ligase, that has increased expression in various anti-cancer drug-resistant cancer cell lines. miRNA array analysis showed the decreased expression of miR-335 in these cells. Targetscan analysis predicted the binding of miR-335 to the 3'-UTR of SIAH2. miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

01 Sep 2010·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

The Ski protein negatively regulates Siah2-mediated HDAC3 degradation

Q3 · BIOLOGY

Article

Author: Nobuhide Ueki ; Hong Ling Zhao ; Michael J. Hayman

Ski acts as a transcriptional co-repressor by multiple direct and indirect interactions with several distinct repression complexes. Ski represses retinoic acid (RA) signaling by interacting with, and stabilizing, key components of the co-repressor complex, namely, HDAC3. However, little is known as to how the Ski protein can stabilize HDAC3. In the present study, we identified the Siah2 protein as a potential E3 ubiquitin ligase that mediated proteasomal degradation of HDAC3. Reciprocal co-immunoprecipitation assays further revealed that Ski interacts with Siah2. Furthermore, co-expression of the Ski protein stabilized the level of Siah2 protein. Since Siah2 regulates its own level of expression by self-degradation, the stabilization of Siah2 by Ski is an indication that Ski association leads to inhibition of Siah2 E3 ubiquitin ligase activity. Only wild-type Ski and Ski truncation mutants that were in the same complex with Siah2 could stabilize HDAC3 levels. Taken together, the results suggest that association with Ski leads to inhibition of Siah2 E3 ubiquitin ligase activity and in this way, the Ski protein inhibits Siah2-mediated proteasomal degradation of HDAC3.

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