Table 1.
Mechanisms of HDACi-induced autophagy and potential mechanisms of resistance.
| Autophagic Regulation | HDACi | Cancer Cell Type | Ref. | Mechanisms of Resistance | Ref. |
|---|---|---|---|---|---|
| mTOR Inhibition | SAHA | ESS-1 | [49,153] | Constitutive PI3K-AKT signaling -AKToverexpression -PI3K mutations -Loss of PTEN, ARHI, LKB-1 -other upstream factors Beclin-1 deficiency Bcl-2 overexpression |
|
| SAHA | Glioblastoma | [136] | |||
| Butyrate, SAHA | HelaS3 | [135,154] | |||
| SAHA, OSU-HAD, C42 | HCC, Hep3B, HepG2 | [139] | [155,156,157,158] | ||
| SAHA | Jurkat T-cells | [137] | |||
| SAHA | Gliobastoma SC | [138] | |||
| Apicidin | Salivary MEC | [134,159] | [160,161,162,163] | ||
| * MGCD0103 | Primary CLL | [151,152] | |||
| * SAHA, TSA, VPA, MS-275, JQ2 | DS-AMKL cells | [64] | |||
| ROS Accumulation | SAHA | Jurkat T-cells | [137] | Increased levels of ROS scavengers/antioxidant enzymes (TRX) | [164,165] |
| SAHA | CMLL | [58] | |||
| FK228 | Gastric carcinoma | [165] | |||
| M-275 | HCT116 | [166] | |||
| VPA, SAHA | AML (Kasumi-1) | [62] | |||
| VPA, TSA | PaCa44, Panc1 | [130] | |||
| p53 Acetylation & Deficiency | Sirtinol | MCF-7 | [131] | Overexpression/GOF of mutant p53 Decreased degradation of p53 (MDM2, HSP90) |
[167,168,169,170,171] |
| MHY2256 | MCF-7 | [132] | |||
| MHY2256 | Endometrial | [133] | |||
| SAHA | ESS-1 | [49] | |||
| VPA, TSA | PaCa44, Panc1 | [130] | |||
| p21 Upregulation | SAHA, H40 | PC-3M, HL-60 | [142] | Deregulated phosphorylation by Akt1 Deregulation by p53 (p53R2; cytoplasmic p21) |
[172,173,174,175] |
| MRJF4 | PC3 | [128] | |||
| Apicidin | Salivary MEC | [134,159] | |||
| VPA, TSA | PaCa44, Panc1 | [130] | |||
| NF-κB Hyper-acetylation | SAHA, MS-275 | PC3 | [141] | (Constitutive) NF-κB upregulation | [176] |
| FOXO1 Transcription | LBH589 | HepG2, HCT116 | [145] | MDR1 upregulation Anti-oxidative enzyme upregulation |
[177,178,179] |
| DAPK Upregulation | SAHA, TSA, LBH589, JQ2 | HCT116 | [147] | DAPK hypermethylation & ubiquitination | [180,181] |
| NRF2 upregulation | SAHA, TSA | Huh-7, MGC-803 | [146] | Aberrant NRF2 expression |
[182,183,184] |
* Suppression of autophagy due to mTOR activation; HDACi, histone deacetylase inhibitor; SAHA, suberoylanilide hydroxamic acid; VPA, valproic acid; TSA, trichostatin A; MGCD0103, mocetinostat; MS-275, etinostat; FK228, romidepsin; LBH589, panobinostat; SC, stem cells; MEC, Mucoepidermoid carcinoma; CLL, chronic lymphocytic leukemia;; DS-AMKL, down syndrome associated acute myeloid leukemia; AML, acute myeloid leukemia; MDM2, mouse double minute 2; TRX, thioredoxin; HSP90, heat shock protein 90.