Table 1.

The role of histone lysine demethylases in head and neck cancers.

Histone Lysine Demethylase	Target Site	Tumor Localization	Significance	Reference
KDM1A (LSD1)	H3K4me1/2 H3K9me1/2	Oral cavity	Involved in the cell cycle and proliferation by modulating E2F signaling. Overexpression is associated with poor clinical outcomes.	[24]
		Tongue	Aberrantly overexpressed in a significant fraction of tongue SCC. High expression promotes cancer cell growth, proliferation, and metastasis as well as correlates with tumor size, pathological grade, and poor prognosis. Involved in the regulation of the microenvironment and EMT.	[23,52,53]
		Esophagus	Expression is higher in esophageal cancer tissues than in normal tissues and correlates with lymphovascular invasion, high tumor stage, and poor prognosis. Involved in cell growth and proliferation. Role in migration, invasion, and EMT. Contributes to Warburg’s effect by promoting glucose uptake and a metabolic shift toward glycolysis.	[61,62,63]
KDM2A (JHDM1A/ FBXL11)	H3K4me3 H3K36me1/2	Tongue	Involved in cancer cell proliferation and tumor progression.	[27]
KDM2B (JHDM1B/ FBXL10)	H3K36me1/2 H3K4me3	Larynx	Overexpressed in a subset of HPV-positive laryngeal squamous cell carcinomas. Associated with c-MYC copy number gain.	[26]
KDM3A (JHDM2A/ JMJD1A/ TSGA)	H3K9me1/2	Oral cavity	Nuclear expression is associated with a 10-fold increase in lymph node metastasis risk.	[55]
		Hypopharynx/larynx	Hypoxia-related regulator of carcinogenesis.	[64]
		Esophagus	Role in hypoxia-related radioresistance and cancer progression.	[29]
KDM4A (JMDM3A/ JMJD2A)	H3K4me3 H3K9me2/3 H3K36me2/3	Oral cavity/ larynx	Involved in immune evasion and invasive growth. Targeting KDM4A enhances anti-PD-1 therapy and eliminates cancer stem cells.	[34]
		Nasopharynx	Overexpression correlates positively with tumor stage, metastasis, and clinical stage. Role in promoting cancer cell proliferation, migration, invasion, and Warburg effect.	[32]
		Larynx/ hypopharynx/oral cavity	Frequently overexpressed compared to normal epithelia. The high abundance of this protein is associated with metastasis, and its depletion reduces the invasive potential of SCC cells. Involved in the regulation of the JUN and FOSL1 expression.	[33]
KDM4C (JMDM3C/ JMJD2C/ GASC1)	H3K4me3 H3K9me1/2/3 H3K36me2/3	Esophagus	Gene frequently amplified in esophageal SCC. Its high expression is associated with poor survival. Role in stemness promotion via NOTCH1 promoter demethylation.	[35,65]
KDM5A (JARID1A/RBP2)	H3K4me2/3 H3K9me1/2	Head and neck	One of the 8 genes amplified in both cell lines and tumors in genomic analysis, involving 39 HNSCC cell lines and 106 HNSCC tumors.	[66]
		Tongue/larynx	Role in the regulation of the EMT and ferroptosis susceptibility.	[67]
KDM5B (JARID1B/ PLU-1)	H3K4me2/3 H3K36me3	Head and neck	Frequently overexpressed in different types of HNSCC. Upregulation is associated with progression parameters, including lymph node metastasis and recurrence. Knockdown results in cell cycle arrest and apoptosis by suppressing Bcl-2 family members.	[40,56]
		Tongue/ Oral cavity	Frequently upregulated with a role in migration, invasion, stemness, EMT, and radioresistance. Its catalytic activity is not required to sustain parts of its prooncogenic functions, like repressing E-cadherin and promoting invasion.	[41,42,68]
		Hypopharynx	Possible role as a tumor suppressor by promoting differentiation and inhibiting proliferation.	[69]
		Esophagus	Downregulation by miR-194 results in inhibition of cancer cells proliferation and invasion along with intensified apoptosis.	[70]
KDM5C (JARID1C/ SMCX)	H3K4me2/3 H3K9me3 H3K27me3	Esophagus	Its inhibition entails upregulation of apoptosis-related genes and reduces cell proliferation.	[71]
KDM6A (UTX)	H3K27me2/3	Head and neck	Its expression is altered in about a third of HNSCC cases. Frequently overexpressed in HPV-positive tumors. Activity of this histone demethylase is required to maintain p16 expression, which is necessary for HPV E7 expressing cancer cells, despite the tumor-suppressing role of p16 in most cancers.	[16,45]
		Esophagus	High expression is associated with a better prognosis, and downregulation increases cell growth and reduces E-cadherin expression. Role in hypoxia-related radioresistance.	[29,72]
		Tongue	Overexpression is associated with a poor prognosis in patients after surgical resection. Involved in the regulation of the cell cycle, EMT, and invasion.	[57]
KDM6B (JMJD3)	H3K9me3 H3K27me2/3	Tongue/hypopharynx	Simultaneous inhibition of LSD1 and JMJD3 impairs cell proliferation and induces apoptosis and senescence.	[59]
		Oral cavity/ tongue/ hypopharynx	Role as a tumor suppressor. Repression by Notch-effector CSL promotes proliferation and tumorigenesis.	[73]
		Esophagus	Overexpression is associated with poor prognosis. Upregulation is especially pronounced in patients with lymph node metastasis. Important role in the regulation of many signaling pathways involved in cancer cells proliferation, stemness, invasion, and susceptibility to therapy.	[46,58,74]
KDM7B (PHF8)	H3K4me3 H3K9me1/2 H4K20me1 H3K27me2	Larynx/ hypopharynx	High expression is associated with shorter survival and disease-free survival. Overexpression correlates positively with T classification, clinical stage, and tumor relapse.	[49]
		Esophagus	Knockdown results in inhibition of cancer cells proliferation, an increase in apoptosis, a reduction of colony formation, and a drop in the number of migratory and invasive cells.	[50]
KDM8 (JMJD5)	H3K4me3 H3K9me3 H3K36me2	Tongue/ Oral cavity/ Larynx	Overexpressed in comparison to normal oral mucosa. Suppression entails reduced cancer cell migration and invasion, at least in part through its involvement in the regulation of EMT. Inhibition promotes apoptosis by regulating the activation of caspases and p53.	[51]
		Tongue	Frequently overexpressed, leading to increased proliferation of cancer cells.	[60]

Abbreviations: EMT—epithelial–mesenchymal transition; HPV—human papilloma virus.