PySAHA

Amino Acid Sequence

3D Structure (/structures/AF-Q13547-F1-model_v6.cif)

Function

Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. As part of the SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription. Also functions as a deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3, STAT3, ZNF76 and TSHZ3. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation. In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase and delactylase by mediating decrotonylation ((2E)-butenoyl) and delactylation (lactoyl) of histones, respectively.

Amino Acid Sequence

3D Structure (/structures/AF-Q92769-F1-model_v6.cif)

Function

Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (By similarity). Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Component of the SIN3B complex that represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2. Also deacetylates non-histone targets: deacetylates TSHZ3, thereby regulating its transcriptional repressor activity. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation (By similarity). Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A. In addition to protein deacetylase activity, also acts as a protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl), lactoyl (lactyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation, delactylation and de-2-hydroxyisobutyrylation, respectively.

Amino Acid Sequence

3D Structure (/structures/AF-Q9UBN7-F1-model_v6.cif)

Function

Deacetylates a wide range of non-histone substrates. Plays a central role in microtubule-dependent cell motility by mediating deacetylation of tubulin. Required for cilia disassembly via deacetylation of alpha-tubulin. Alpha-tubulin deacetylation results in destabilization of dynamic microtubules (By similarity). Promotes deacetylation of CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy. Deacetylates SQSTM1. Deacetylates peroxiredoxins PRDX1 and PRDX2, decreasing their reducing activity. Deacetylates antiviral protein RIGI in the presence of viral mRNAs which is required for viral RNA detection by RIGI. Sequentially deacetylates and polyubiquitinates DNA mismatch repair protein MSH2 which leads to MSH2 degradation, reducing cellular sensitivity to DNA-damaging agents and decreasing cellular DNA mismatch repair activities. Deacetylates DNA mismatch repair protein MLH1 which prevents recruitment of the MutL alpha complex (formed by the MLH1-PMS2 heterodimer) to the MutS alpha complex (formed by the MSH2-MSH6 heterodimer), leading to tolerance of DNA damage. Deacetylates RHOT1/MIRO1 which blocks mitochondrial transport and mediates axon growth inhibition. Deacetylates transcription factor SP1 which leads to increased expression of ENG, positively regulating angiogenesis. Deacetylates KHDRBS1/SAM68 which regulates alternative splicing by inhibiting the inclusion of CD44 alternate exons. Deacetylates PRDM16 (By similarity). Acts as a valine sensor by binding to valine through the primate-specific SE14 repeat region. In valine deprivation conditions, translocates from the cytoplasm to the nucleus where it deacetylates TET2 which promotes TET2-dependent DNA demethylation, leading to DNA damage. Promotes odontoblast differentiation following IPO7-mediated nuclear import and subsequent repression of RUNX2 expression. In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and targets them to the aggresome, facilitating their clearance by autophagy. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer.

Description

Considering the demonstrated dual efficacy of PySAHA as both a potent HDAC degrader and a photodynamic therapy agent, we next evaluated its anti-proliferative activity in MCF-7 cells. As shown in Fig. 3C, treatment with PySAHA for 48 hours resulted in a significant reduction in cell viability, with an IC50 value of 6.2±0.8μM. Remarkably, PDT activation via light irradiation (10 or 20 minutes) enhanced the compound’s cytotoxicity in a time-dependent manner, reducing the IC50 to 2.0±0.9 μM and 0.7±0.2 μM, respectively.

Description

We also tested the toxicity of PySAHA on mammary epithelial (MCF-10A) cells, and the results revealed that its IC50 for inhibiting the proliferation of MCF10A cells was 25.7±4.4 μM, indicating a favourable therapeutic window (Fig. S5, ESI†).

Description

We further evaluated the HDAC inhibitory activity of PySAHA using HDAC6 as the model enzyme (Fig. S1, ESI†) . The enzymatic assay revealed that PySAHA demonstrated potent inhibitory activity against HDAC6 with an IC50 value of 67.57 nM, which is in the same order of magnitude as the reference compound SAHA (IC50 = 12.62 nM).

Description

Light irradiation alone (10 min at 460 nm) produced no measurable antitumor effect, as tumor progression in this cohort closely paralleled that of the vehicle group. Administration of PySAHA significantly attenuated tumor growth, with final volumes reaching 478mm3. This corresponded to a robust tumor growth inhibition (TGI) of 81.2%, demonstrating the compound’s potent intrinsic anticancer activity. Most notably, combinatorial treatment with PySAHA and light irradiation induced tumor regression, reducing the mean volume from 340 mm3 to 245 mm3 . This remarkable response translated to a TGI of 108.0%, indicating active tumor shrinkage.