Concept of histone deacetylases in cancer: Reflections on esophageal carcinogenesis and treatment

Table 1 Histone deacetylase-associated mechanisms of action in carcinogenesis

Increased expression of genes associated with the cell cycle, increasing proliferation, by overpassing the G1-S checkpoint, either by increasing CDK-2 and -4[12], or by inhibiting p21 protein that arrests cell cycle[13].

Inhibition of both the intrinsic and extrinsic apoptotic pathways[15].

Acyl group removal from other non-histone proteins, like transcription factors and regulatory proteins, indirectly affecting cellular proliferation[8].

Increased macropinocytosis, a process closely related to cellular migration and increased metastatic potential[19].

Increased chemotherapy resistance in tumor cells[21].

Protection from cellular damage caused by ROS[22].

Inhibition of angiogenesis by decreasing VEGF and HIF-1α[22].

Reduction of E-cadherin and increased vimentin expression, increasing metastatic potential[12].

Increased HSP function, conferring stability to oncogenic proteins[33].

Decreased function of DNA repair enzymes[39].

CDK: Cyclin dependent kinases; ROS: Reactive oxygen species; VEGF: Vascular endothelial growth factor; HIF-1α: Hypoxia inducible factor 1-alpha; HSP: Heat-shock proteins.

Table 2 Studies on the association of histone deacetylase involvement in esophageal cancer

Ref.	Year	Number of pathology samples	HDACs/HATs studied	Correlation with clinicopathological data
Langer et al[29]	2010	180 EC samples	HDAC1 and 2	Increased N stage and Tumor Grade correlated with increased HDAC2 expression
Xue et al[30]	2014	167 EC samples	HDAC1 and HAT1	Increased Tumor Grade correlated with increased HAT1 expression
Zeng et al[12]	2016	86 ESCC samples	HDAC4	Increased T, N, M, TNM stage, Tumor Grade and increased metastatic potential correlated with increased HDAC4 expression Worse 5-yr OS and DFS was noted in patients with increased HDAC4 expression
Tao et al[33]	2018	Study performed on cell lines of EC	HDAC6	Increased cell motility and invasion capacity and increased HSP-90 activity, conferring oncogenic protein stability, correlated with increased HDAC6 expression

HDACs: Histone deacetylases; HATs: Histone acetyltransferases; EC: Esophageal cancer; ESCC: Esophageal squamous cell carcinoma; OS: Overall survival; DFS: Disease free survival.