Table 1.
Natural flavonoids targeting HDAC in human cancers.
| Molecules (Origins) |
Used Models | Methods | Key Findings | Ref. |
|---|---|---|---|---|
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | MCF-7 and MDA-MB-231 (Breast cancer cells) | Flow cytometry (apoptosis assay) RT-PCR and real-time PCR (Quantification of hTERT expression) DNMTs, HDACs, and HATs activity assays ChIP assay Western blot analysis |
Inhibited the transcription of hTERT through epigenetic mechanisms in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells. Inhibited the activities of DNMT and histone acetyltransferase (HAT). Remodelled the chromatin structures of the hTERT promoter by decreasing the level of acetyl-H3, acetyl-H3K9, and acetyl-H4 in the hTERT promoter. Induced chromatin alterations that facilitated the binding of many hTERT repressors such as MAD1 and E2F-1 to the hTERT regulatory region. |
[189] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | A431 (Human skin cancer) | DNA methylation assay HDAC activity assay Western blot analysis Cell lysates |
Decreased global DNA methylation levels in A431 cells in a dose-dependent manner. Decreased the HDAC activity. Increased the levels of acetylated lysine 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysine 5, 12, and 16 on histone H4. Re-expressed the mRNA and proteins of silenced tumor suppressor genes, p16INK4a and Cip1/p21. |
[190] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | HT-29 and HCT 116 (Human colon cancer cell lines) | Western blot analysis RNA extraction Real-time PCR |
Reduced HDAC and DNMT protein expression. Decreased HDAC2 and HDAC3 expressions. Decreased association between UHRF1 and DNMT3. Decreased association between UHRF1 and HDAC3 in only the HCT 116 cell line. |
[187] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | MCF7 and MDA MB 231 (Breast cancer cells) | RT-PCR Western blot analysis |
Lowered the protein levels of DNMT1, HDAC1, and MeCP2. | [204] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | HT29 (Human colon cancer cells) | HDAC enzyme activity Western blot |
Inhibited the HDAC activity in intact HT29 cells. Decreased the HDAC1 protein level. |
[188] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Not reported) | MCF-7 and MDA-MB-231 (Breast cancer cells) | RNA extraction RT PCR ChIP method Western blot analysis |
Reduced levels of the enhancer of zeste homolog 2 (EZH2) and Class I HDAC proteins. | [205] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | CRL-2577, HCT-116 and HT-29HTB-38 cells | Cell viability and apoptosis Real-time quantitative PCR HDAC activity assessment ChIP assay |
Combinatorial effects of EGCG and NaB. Increased HDAC1 in RKO CRC cells. Inhibited the HDAC1, DNMT1, and survivin in all the three CRC cells tested. Affected the global DNA methylation. |
[206] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | HeLa cells | HDAC activity assessment Bisulfite modification MS-PCR RT-PCR |
Decreased the HDAC activity time-dependently. Zn ion was taken to be the substrate-binding site of HDAC1. |
[207] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | A549/DDP cell line | Cell viability assay MTT assay RT- PCR Total HDAC activity and DNMT activity in vivo experiments |
In vitro EGCG + cisplatin (DDP) treatment caused: Inhibition of DNMT and HDAC activities, reversal of hypermethylated status, and downregulation of the expression of GAS1, TIMP4, ICAM1, and WISP2 gene in A549/DDP cells. In vivo EGCG + DDP pre-treatment caused: Inhibition of tumors, a decrease in methylation levels of GAS1, TIMP4, ICAM, and WISP2, and an increase in their expression levels. |
[208] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Not reported) | APL NB4 and HL-60 cells | RT-qPCR ChIP assay MSP and sequencing Western blot analysis |
Downregulated the epigenetic modifiers HDAC1 and HDAC2 Downregulated the polycomb repressive complex 2 (PRC2) core components in gene and protein levels. Reduced gene-binding effect of core components of EZH2, SUZ12, and EED. |
[209] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Not reported) | DUPRO and LNCaP (prostate cells) | RNA extraction RT– semi q-PCR Western blot analysis ChIP assay HDAC enzyme activity |
Reduced the expression of both EZH2 enhancers and its catalytic product trimethylation of H3. Increased acetylation of histone H3K9/18. Reduced the activity of Class I HDACs, as well as EZH2 and H3K27me3 levels. |
[210] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Not reported) | HMEC-1 and HUVECs cells | Cell proliferation assay RNA isolation Reverse transcription and RT- PCR Western blot analysis HDAC Activity Assay |
Increased histone acetylation (H3K9/14ac, H3ac), as well as methylation of both active (H3K4me3) and repressive (H3K9me3) chromatin. Inhibited HDAC activity in both cellular and cell-free models. Altered epigenome modulator expression and activity (HDAC5 and 7, p300, CREBP, LSD1 or KMT2A). |
[191] |
| (−)-Epigallocatechin-3-gallate (EGCG) (Purchased) | Breast cancer cells | RNA extraction Protein extraction qRT-PCR Western blot analysis ChIP assay HDAC activity HMT (H3K27me3) activity |
Induced changes in histone modifications. Resulted in an increased apoptosis. | [211] |
| Delphinidin (Purchased) | JB6 P+ (Mouse epidermal cells) HepG2–C8 (hepatocellular cancer cells) |
Western blot Quantitative real-time PCR Bisulfite genomic sequencing |
Reduced DNMTs and HDACs protein expression. | [212] |
| Apigenin (Purchased) | Human prostate cancer cell lines 22Rv1 and PC-3 (prostate cancer cells) | HDAC activity assessment RNA isolation RT-PCR and q-PCR Western blot analysis ChIP assay Tumor xenograft studies |
Inhibited Class I HDACs in prostate cancer cells. Inhibited HDAC enzyme activity, particularly HDAC1 and HDAC3. Induced histone acetylation. Increased p21/waf1 protein and mRNA expression, as well as p21/waf1 mRNA expression. Reduced (in vivo) tumor development, HDAC activity, HDAC1, and HDAC3 protein expression. |
[192] |
| Apigenin (Purchased) | JB6 P+ (Skin cells) | RT-PCR Western blot analysis |
Reduced some HDACs (1–8) and their expression levels. | [213] |
| Apigenin (Purchased) | MDA-MB-231 (breast cancer cells) | Immunoblot analysis HDAC assay Nuclear extract preparation ChIP assay |
Inhibited HDAC activity. Induced acetylation of histone H3. Increased the acetylation of histone. |
[193] |
| Galangin (Purchased) | Neuroblastoma cells | Flow cytometry ELISA RT-PCR and qPCR Western blot analysis ChIP assay DNA methylation analysis |
Reduced the BACE1 at mRNA and protein levels. Reduced acetylated H3 in BACE1 promoter areas by increasing endogenous HDAC1-mediated deacetylation. |
[194] |
| Genistein (Purchased) | Human esophageal squamous cell carcinoma cell lines KYSE 510 and KYSE 150 cancer cells |
Modification by bisulfite Methylation-specific PCR RT-PCR |
Reversed DNA hypermethylation. Reactivated RARβ, p16INK4a, and MGMT in KYSE 510 cells. Reversed DNA hypermethylation and reactivated RARβ in KYSE 150 cells and prostate cancer LNCaP and PC3 cells. Activated RARβ. Inhibited the activity of HDAC. |
[195] |
| Genistein (Purchased) | MCF7 and MDA MB 231 (Breast cells) | Bisulfite conversion RT-PCR Western blot |
Reduced HDAC1 and MeCP2 protein levels. | [204] |
| Genistein (Purchased) | A498, ACHN, HEK-293 and HK-2 cells | RT-PCR Sodium bisulfite modification and sequencing HAT and HDAC analysis |
Increased HAT activity and reduced HDAC activity. | [205] |
| Genistein (Purchased) | LNCaP, PC3, and RWPE-1 (Prostate cells) | Quantitative RT-PCR Sodium bisulfite modification and sequencing ChIP analysis HAT and HDAC analysis |
Increased the levels of acetylated histones 3, 4, histone three dimethylated at lysine 4, histone 3 trimethylated at lysine 4, and RNA polymerase II. Decreased DNA methyltransferase and methyl-binding domain protein 2 activity. Increased HAT activity. |
[196] |
| Genistein (Purchased) | HT29 (colon cancer cells) | HDAC enzyme activity Western blot analysis |
Inhibited HDAC activity in intact HT29 cells. Reduced HDAC1 protein levels. |
[188] |
| Genistein (Purchased) | MCF-7, MDA-MB-231, and MDA-MB-157, HMECs cells, and two mouse models | MTT assay RT-PCR ChIP assay |
Reduced the activity of HDAC, alone or in combination with TSA. Reduced binding to the ERα promoter, as well as gene expression for HDACs. Reduced HDAC1 protein and mRNA expression in both animal models studied. |
[197] |
| Genistein (Purchased) | Rat colon tissues | RNA isolation qPCR analysis ChIP analysis Bisulfite sequencing |
In the post-AOM phase, there was a decrease in H3Ac at the promoter of Wnt5a, Sfrp5, and Sfrp2. Repressed histone H3 lysine 9 methylation and serine 10 phosphorylation at the promoters of Sfrp2, Sfrp5, and Wnt5a in the post-AOM period. In the post-AOM period, the nuclear level of HDAC3 protein was increased. After AOM induction, H3Ac was reduced in the same region of the Sfrp5 promoter. |
[198] |
| Genistein (Purchased) | MCF-7 and MDA-MB-231 cells | HDAC activity assay HMT activity |
Inhibition of HDAC and HMT by GEN + SFN. Downregulation of HDAC2 and HDAC3 levels at the mRNA and protein levels. GEN + SFN downregulated the hTERT levels. |
[214] |
| Genistein (Purchased) | Human cervical cancer cells | DNMT and HDAC activity analysis In silico studies in the post-AOM period |
Reduced the expression of HDAC and enzymatic activity in a time-dependent manner. Interacted with members of the DNMT and HDAC families. Reversed the tumor suppressor genes’ promoter region methylation, and their expression was restored. |
[215] |
| Genistein (Purchased) | HeLa cells | qPCR HDAC activity assay HMT-H3K9 activity Global DNA methylation |
Altered HDACs, HMTs, demethylases, and histone phosphorylases’ expression. Reduced HDAC and HMT activity, as well as global DNA methylation levels. |
[203] |
| Kaempferol (Not reported) | HepG2, Hep3B, and HCT-116 cells | In silico docking analysis HDACi screening assay HDAC inhibition profiling Immunoblotting Real-time cell monitoring |
Inhibited the activity of HDAC. Induced hyperacetylation of histone complex H3. Reduced cell viability and proliferation rate. |
[201] |
| Luteolin (Purchased) | MDA-MB231-1833, LNM35, HT29, HepG2, and MCF7/6 cells | HDAC assay and histone acetylation levels | Inhibited HDAC activity. | [216] |
| Luteolin (Purchased) | HCT116 (Colorectal cells) | HDAC activity assay | Reduced levels of HDAC protein and enzyme activity. | [217] |
| Pectolinarigenin (Purchased) | 143B, HOS, and MG63 (Osteosarcoma) | Western blot analysis RT-PCR ChIP assay MTS cell viability assay |
Disrupted the development of the STAT3/DNMT1/HDAC1 complex. Caused an increase in SHP-1 expression in osteosarcoma. |
[218] |
| Pelargonidin (Purchased) | Skin epidermal JB6 (JB6 P+) cells | Western blot analysis RT-PCR Bisulfite genomic sequencing |
Reduced protein levels of genes encoding HDACs. | [219] |
| Silibinin (Not reported) | H1299 cells | HDAC activity RT- RT-PCR assay |
Reduced the activity of HDAC in a dose-dependent manner. Reduced HDAC1, HDAC2, and HDAC3 protein levels, whereas HDAC1, HDAC6, SET domain proteins (SETD1A, D4, D6) and lysine-specific demethylases were upregulated (KDM 5B, 5C, 4A). |
[199] |
| Silibinin (Purchased) | SW480 and SW620 (Colon cells) | HDAC activity | No effect on the activity of HDACs. | [220] |
| Silibinin (Purchased) | DU145 and PC3 (Prostate cells) | Western blot analysis RT-PCR HDACs assay |
Reduced HDAC1-2 expression levels in a concentration-dependent manner. | [200] |
| Taxifolin (Purchased) | HepG2 cells, skin epidermal JB6 P+ cells, and HepG2-C8 cells | Western blot analysis RNA extraction qRT-PCR assay Bisulfite genomic sequencing |
Inhibited DNMT and HDAC protein expression. | [221] |
| Quercetin (Purchased) | HL-60 (leukemia cells) | Western blot analysis RT-PCR HDAC assay HAT assay ChIP assay |
Increased histone H3 acetylation, which promoted the production of FasL Activated HAT and inhibited HDAC. |
[202] |
| Quercetin (Purchased) | Hamster buccal pouch (HBP) carcinomas | Immunohistochemistry Western blot analysis RT-PCR |
Inhibited HDAC-1 and DNMT1 activities. | [222] |
| Quercetin (Purchased) | Eca9706 cells | MTT assay Immunoblotting MSP of p16INK4a gene promoter |
Reduced the reverse expressions of global HDAC1. Quercetin + butyrate displayed a reverse effect targeting both altered DNA methylation and histone acetylation, acting as HDAC inhibitor mediated via epigenetic-NF-κB cascade signaling. |
[223] |
| Quercetin (Purchased) | HeLa cells | DNMT and HDAC activity assay HMT-H3K9 activity assay Molecular modeling qRT-PCR |
Reduced the activity of HDAC activity. Reduced the activation of HMT-H3K9. Modified the expression of many chromatin modifiers, and lowered the activity of HDACs and HMTs. Several DNMTs and HDACs interacted with residues in their catalytic cavities (as a competitive inhibitor). |
[203] |