Emerging Roles of Epigenetic Regulator Sin3 in Cancer

Bansal, Nidhi; Gourichon, David; Farías, Eduardo; Waxman, Samuel

doi:10.1016/bs.acr.2016.01.006

Cited by 51 publications

(58 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As many groups are developing therapeutic strategies for metastasis, we provide here a caution for two proteins that have been thought to be very similar with regard to sequence, protein-protein interactions, and function. SIN3 has recently gained interest as a potential drug target [7, 8]. The studies presented here could prove meaningful during the developmental drug discovery pipeline and provide a foundation for moving forward with relevant target identification for metastatic breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…A key epigenetic regulator that is required for normal development and has been implicated in breast cancer progression is SIN3 (Switch-Independent 3) [7, 8]. SIN3 is a scaffolding protein that regulates gene transcription through chromatin modification by recruiting histone deacetylases (HDACs) to function at particular sites of the genome, typically leading to transcriptional silencing although several genes have been shown to be activated [9–11].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SIN3A and SIN3B differentially regulate breast cancer metastasis

et al. 2016

View full text Add to dashboard Cite

SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SIN3A and SIN3B differentially regulate breast cancer metastasis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Here we present a medium-throughput strategy applied to investigating interactions among components of the Sin3 complex, an important regulator of global gene expression (6). Clarifying the precise role of Sin3 components in controlling critical cellular processes is important as abnormal Sin3 function is associated with carcinogenesis (7). Notably, SIN3A, the gene encoding the key scaffolding protein around which Sin3 complexes are built, was recently identified as one of the top 127 significantly mutated genes across common cancer types (8).…”

mentioning

confidence: 99%

A Structured Workflow for Mapping Human Sin3 Histone Deacetylase Complex Interactions Using Halo-MudPIT Affinity-Purification Mass Spectrometry

Banks

Thornton

Eubanks

et al. 2018

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Although a variety of affinity purification mass spectrometry (AP-MS) strategies have been used to investigate complex interactions, many of these are susceptible to artifacts because of substantial overexpression of the exogenously expressed bait protein. Here we present a logical and systematic workflow that uses the multifunctional Halo tag to assess the correct localization and behavior of tagged subunits of the Sin3 histone deacetylase complex prior to further AP-MS analysis. Using this workflow, we modified our tagging/expression strategy with 21.7% of the tagged bait proteins that we constructed, allowing us to quickly develop validated reagents. Specifically, we apply the workflow to map interactions between stably expressed versions of the Sin3 subunits SUDS3, SAP30, or SAP30L and other cellular proteins. Here we show that the SAP30 and SAP30L paralogues strongly associate with the core Sin3 complex, but SAP30L has unique associations with the proteasome and the myelin sheath. Next, we demonstrate an advancement of the complex NSAF (cNSAF) approach, in which normalization to the scaffold protein SIN3A accounts for variations in the proportion of each bait capturing Sin3 complexes and allows a comparison among different baits capturing the same protein complex. This analysis reveals that although the Sin3 subunit SUDS3 appears to be used in both SIN3A and SIN3B based complexes, the SAP30 subunit is not used in SIN3B based complexes. Intriguingly, we do not detect the Sin3 subunits SAP18 and SAP25 among the 128 high-confidence interactions identified, suggesting that these subunits may not be common to all versions of the Sin3 complex in human cells. This workflow provides the framework for building validated reagents to assemble quantitative interaction networks for chromatin remodeling complexes and provides novel insights into focused protein interaction networks.

show abstract

“…We focused on the histone acetyltransferase (HAT) p300, deacetylase HDAC2 and co-factor Sin3A. Unlike p300 and HDACs, Sin3A does not have enzymatic activity and is devoid of intrinsic DNA binding ability 14 . Sin3A is mostly associated with HDACs to form a “co-repressor” 15 but can also form a “co-activator” with p300 16 (see below).…”

Section: Resultsmentioning

confidence: 99%

Chromatin remodeling system p300-HDAC2-Sin3A is involved in Arginine Starvation-Induced HIF-1α Degradation at the ASS1 promoter for ASS1 Derepression

Tsai

Long

Chang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Argininosuccinate synthetase 1 (ASS1) is the key enzyme that controls biosynthesis of arginine (Arg). ASS1 is silenced in many human malignancies therefore, these tumors require extracellular Arg for growth. The Arg-degrading recombinant protein, pegylated arginine deiminase (ADI-PEG20), has been in clinical trials for targeting Arg auxotrophic tumors by Arg starvation therapy. Resistance to Arg starvation is often developed through reactivation of ASS1 expression. We previously demonstrated that ASS1 silencing is controlled by HIF-1α and Arg starvation-reactivated ASS1 is associated with HIF-1α downregulation. However, mechanisms underlying ASS1 repression and HIF-1α turnover are not known. Here, we demonstrate that interplay of p300-HDAC2-Sin3A in the chromatin remodeling system is involved in HIF-1α degradation at the ASS1 promoter. The histone acetyltransferase p300 is normally associated with the ASS1 promoter to maintain acetylated H3K14ac and H3K27ac for ASS1 silencing. Arg starvation induces p300 dissociation, allowing histone HDAC2 and cofactor Sin3A to deacetylate these histones at the ASS1 promoter, thereby facilitating HIF-1α-proteasomal complex, driven by PHD2, to degrade HIF-1α in situ. Arg starvation induces PHD2 and HDAC2 interaction which is sensitive to antioxidants. This is the first report describing epigenetic regulation of chromosomal HIF-1α turnover in gene activation that bears important implication in cancer therapy.

show abstract

Emerging Roles of Epigenetic Regulator Sin3 in Cancer

Cited by 51 publications

References 77 publications

SIN3A and SIN3B differentially regulate breast cancer metastasis

SIN3A and SIN3B differentially regulate breast cancer metastasis

A Structured Workflow for Mapping Human Sin3 Histone Deacetylase Complex Interactions Using Halo-MudPIT Affinity-Purification Mass Spectrometry

Chromatin remodeling system p300-HDAC2-Sin3A is involved in Arginine Starvation-Induced HIF-1α Degradation at the ASS1 promoter for ASS1 Derepression

Contact Info

Product

Resources

About