KDM1 family and cancer
The KDM1 family consists of KDM1A (also named LSD1) and KDM1B (also named LSD2). Both KDM1A and KDM1B have a FAD-dependent amine oxidase domain and SWIRM domain. Furthermore, KDM1A also contains a Tower domain, which is responsible for protein interaction (28). The FAD-dependent amine oxidase domain is responsible for removing a methyl group from monomethylated (me1) or dimethylated (me2) lysine residues, while the SWIRM domain is responsible for assisting demethylation. Both KDM1A and KDM1B are able to catalyze the demethylation of H3K4 with mono-methylation or di-methylation (H3K4me1/me2) (29). However, apart from demethylating H3K4me1/me2, KDM1A is also able to catalyze H3K9me1/me2 demethylation (30,31).
In general, KDM1A was indicated to be overexpressed and associated with poor prognosis in a variety of cancers, indicating the oncogenic role of KDM1A (32–35). Therefore, numerous studies have been performed to elucidate how KDM1A contributes to cancer development and progression. First, KDM1A was reported to regulate the cell cycle, which in turn modulated tumor growth. In an early study, KDM1A was indicated to remove dimethylation at the K370 of p53 to inhibit its interaction with p53 binding protein 1, thus inhibiting apoptosis and promoting tumor cell growth (36). In addition, KDM1A-dependent demethylation of myosin phosphatase target subunit 1 (MYPT1) destabilized MYPT1 and reduced its expression level. Thus, downregulation of MYPT1 led to retinoblastoma protein 1 phosphorylation, finally enhancing the G1/S transition of cancer cells (37). In addition, KDM1A has the ability to reduce hypoxia-inducible factor 1α (HIF-1α) degradation and maintain HIF-1α protein levels, thus promoting tumor growth (38). Furthermore, it was recently reported that the immune landscape is regulated by KDM1A by modulating the expression of immune checkpoint regulators and related chemokines, such as PD-L1, C-C motif chemokine ligand 5, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL10 (39). Apart from these three most studied mechanisms, a variety of downstream genes regulated by KDM1A (E2F1, STAT3 and AGO2) were identified to participate in cancer development (35).
Unlike KDM1A, only a small number of studies have identified the role of KDM1B in cancer. KDM1B is overexpressed in cancers, such as breast cancer (40), colorectal cancer (41) and lung cancer (42), functions in tumor growth and correlates with poor prognosis by catalyzing H3K4 demethylation (43). According to the limited literature, the ability of KDM1B to inhibit apoptosis in a demethylation-dependent manner is the key mechanism for tumor growth and progression (40,41,43,44).
KDM2 family and cancer
KDM2A and KDM2B belong to the KDM2 family, the early discovered JmjC domain-containing proteins. Both KDM2A and KDM2B have a JmjC domain and one plant homeodomain (PHD) (29). However, KDM2A has H3K36me2 demethylation activity, while KDM2B demethylates H3K4me3 and H3K36me2 (18,45). KDM2A and KDM2B were indicated to be overexpressed in cancer tissues and contribute to tumor growth and progression in various malignancies, including colorectal cancer, gastric cancer, ovarian cancer and cervical cancer (46–55).
KDM2A mediates H3K36me2 demethylation at the histone deacetylase 3 (HDAC3) promoter, thereby suppressing HDAC3 expression and promoting carcinogenesis and invasiveness of lung cancer (56). Similarly, KDM2A was observed to repress dual-specificity phosphatase 3 (DUSP3) expression through KDM2A-dependent H3K36me2 demethylation at the DUSP3 promoter, which enhanced the ERK1/2 signaling pathway and facilitated lung tumorigenesis (25). In breast cancer, KDM2A promoted cancer stemness and angiogenesis through the upregulation of signaling molecules, such as Jagged1 and Notch receptor 1 (NOTCH1), in a demethylation-dependent manner, hence leading to poor prognosis (57). Likewise, recent research has also indicated that higher KDM2A expression in cancer-associated fibroblasts is associated with advanced tumor stage and poor survival in patients with breast cancer (58).
KDM2B was able to epigenetically suppress the expression of Mps1 binding protein, an important component of the Hippo pathway, contributing to the progression of pancreatic cancer and leading to poor prognosis (59). In addition, among lung and pancreatic cancer cell lines, KDM2B participates in TGF-β induced epithelial-mesenchymal transition, contributing to cancer invasion and metastasis (60). In malignant hematopoiesis, knocking down of KDM2B markedly reduced cell proliferation in vitro. Furthermore, knocking down KDM2B delayed or even abrogated leukemogenesis in humanized xenograft models (61). Several studies have indicated the oncogenic role of KDM2B. However, one study identified the tumor-suppressive effect of KDM2B, as silencing of KDM2B triggered invasion of breast cancer cell lines (62).
KDM3 family and cancer
The KDM3 family is composed of three components: KDM3A (also named JMJD1A), KDM3B (also named JMJD1B) and KDM3C (also named JMJD1C). All of the three demethylases contain a JmjC domain at the C terminal, a zinc-finger domain and an LXXLL motif. The JmjC domain is responsible for histone demethylation, while the zinc-finger domain and LXXLL motif are separately responsible for DNA binding and nuclear receptor interaction (63). Among these demethylases, KDM3A and KDM3B were observed to specifically demethylate H3K9me1/me2 in vitro and in vivo, whereas KDM3C mainly demethylated H3K9me2 (64–67). Most studies performed to date indicate the oncogenic role of the KDM3 family in various cancer types.
In colorectal cancer, upregulation of KDM3A was indicated to be associated with tumorigenesis, advanced stage and poor prognosis (68,69). To achieve this effect, KDM3A specifically demethylates H3K9me2, promoting Wnt/β-catenin pathway activation in vitro (70). In addition, H3K9me2 demethylation of the Hippo pathway was facilitated by KDM3A and contributed to colorectal cancer tumorigenesis (71). Among breast cancers, KDM3A is essential for the tumorigenic growth of cancer stem cells and promotes invasion by demethylating p53-K372me1 and inhibiting p53 transcription (72). In another study focusing on breast cancer, KDM3A was indicated to increase estrogen receptor (ER) activity via demethylation of H3K9me2/1 and activation of ER target genes, therefore facilitating tumor growth (73). Apart from colorectal cancer and breast cancer, the oncogenic role of KDM3A was observed in prostate cancer (74–76), lung cancer (77,78), pancreatic cancer (79), liver cancer (80,81) and Ewing sarcoma (82,83) through a variety of in vivo and in vitro experiments.
To date, research on the relationship between KDM3B and cancer is limited. In HepG2 cells, the expression of cyclin D1 decreased significantly, the cell cycle was mostly halted in the G2/M phase and cell proliferation was reduced when KDM3B was knocked down (84). In addition, loss of KDM3B was associated with slower growth of castration-resistant prostate cancer cells, although it did not alter the androgen receptor signaling pathway (85). Recently, KDM3B was observed to activate the Wnt/β-catenin signaling pathway, further enhancing the invasion and metastasis of breast cancer (86). In hematopoietic malignancies, KDM3B is recruited to the LIM domain-only protein 2 (lmo2) promoter and transcriptionally activates lmo2, a hematopoietic oncogene that promotes leukemogenesis (87). By contrast, a recent study indicated that KDM3B is highly expressed in patients with acute myeloid leukemia (AML) with favorable prognoses, although KDM3B is highly expressed in hematopoietic malignancies compared to solid tumors. Further examination suggested that KDM3B has an important role in maintaining the fusion protein promyelocytic leukemia/retinoic acid receptor-α levels and the chromatin state during cell differentiation in a demethylation-dependent manner, thus inhibiting acute promyelocytic leukemia progression (88).
Of note, the oncogenic effects of KDM3C on solid tumors and hematopoietic malignancies were identified, although only a small number of studies on KDM3C exist. In AML, KDM3C was able to be recruited by the fusion gene runt related transcription factor 1 (RUNX1)/RUNX1 partner transcriptional co-repressor 1 and demethylated H3K9me2, thus maintaining expression of the fusion gene and its targeting genes, such as p21, fms related receptor tyrosine kinase 1 and serine/threonine/tyrosine kinase 1, and increasing AML cell proliferation (65). Similarly, the use of small molecular modulators of KDM3C, which significantly decreased KDM3C expression, was able to effectively inhibit AML cell growth (89). Among esophageal and colorectal cancers, KDM3C epigenetically sustained the expression of yes-associated protein 1 (YAP1) and activating transcription factor 2 separately and promoted tumor growth and metastasis (90,91).
KDM4 family and cancer
KDM4A (also named JMJD2A), KDM4B (also named JMJD2B), KDM4C (also named JMJD2C), KDM4D (also named JMJD2D), KDM4E (also named JMJD2E) and KDM4F belong to the KDM4 family. Of these, KDM4A, KDM4B and KDM4C have catalytic JmjN and JmjC domains, and non-catalytic PHD and Tudor domains, whereas KDM4D only has catalytic domains (92). The KDM4 family has the ability to catalyze the demethylation of H3K9me2/me3 and H3K36me2/me3 (13,92). In a previous study, the KDM4 family, except for KDM4E and KDM4F with unclear functions in cancer, is mainly overexpressed and acts as oncogenes in different cancer cell lines and tissues (93–96).
KDM4A has a critical role in tumor growth and invasion. KDM4A-mediated H3K9 demethylation has been reported to contribute to androgen receptor activation and affect transcriptional activation through demethylating H3K9me2/me3 (13). In another study, researchers corroborated that KDM4A is responsible for the epigenetic upregulation of YAP1 through recruitment by ETS variant transcription factor 1, ultimately promoting tumor growth in prostate cancer (97). In lung cancers, KDM4A upregulated distal-less homeobox 5, thereby activating the expression of the Myc gene and the downstream Wnt/β-catenin signaling pathway to promote the growth, metastasis and the occurrence of lung cancer (98). In gastric cancer, KDM4A was also observed to promote tumor growth by suppressing apoptosis (99).
KDM4B is both functionally and structurally homogeneous to KDM4A. However, the mechanism by which KDM4B contributes to tumor growth, invasion and metastasis is not similar to that of KDM4A. KDM4B was able to be upregulated by HIF-α, further promoting G2/M phase transition by upregulating cyclin A1 (CCNA1) and downregulating WEE1 G2 checkpoint kinase. KDM4B was also able to promote G1 phase transition by epigenetically downregulating CCND1 through demethylating H3K9me2/me3, ultimately promoting the proliferation of breast cancer (100). This process of KDM4B regulation was also effective in promoting colorectal cancer growth (101). On the other hand, recent studies have emphasized the significance of KDM4B in inducing glucose uptake in tumor growth and progression (102,103). After the knockdown of KDM4B, H3K9me3 levels at the promoter of glucose transporter 1 (GLUT1) increased; thus, the expression of GLUT1 decreased, leading to a reduction in glucose uptake in colon cancer cells (104).
KDM4C was able to remove the methyl group from H3K9me2/me3. When accompanied by KDM1A, KDM4C contributed to altering the expression of genes related to the androgen receptor and promoting prostate carcinogenesis (105). A recent study indicated that KDM4C served as an oncogene in glioblastoma with a dual function of inactivating p53 by demethylating p53K372me1 and activating c-Myc by directly binding to its promoter (106). In addition, similar to KDM4B, KDM4C was also able to remove methyl groups of H3K9 on HIF-α and promote tumor growth (107–109).
KDM4D is able to activate the HIF pathway (110,111) via demethylation of H3K9me3 and H3K36me3 (110) at the promoter region, activate downstream regulatory networks, and promote tumor initiation and progression. Through demethylation of H3K9me3 on the promoters of Hedgehog target genes or β-catenin target genes and activating Hedgehog or β-catenin signaling pathways, KDM4D was able to promote tumor proliferation, progression and invasion (112,113). Furthermore, KDM4D was able to directly antagonize p53 and inhibit p53 binding to its target gene in a demethylase-independent manner; as a result, it functions as an oncogene in liver cancer (114).
KDM5 family and cancer
The KDM5 family includes four members, KDM5A (also named JARID1A), KDM5B (also named JARID1B), KDM5C (also named JARID1C), and KDM5D (also named JARID1D), having highly similar structures. All members contain five domains: JmjC, JmjN, a zinc finger an ARID (DNA-binding domain), as well as a PHD (histone-binding domain) lining between JmjC and JmjN (115,116). Thus, all four members were able to demethylate H3K4me2/me3 and participate in the epigenetic regulation of biological processes related to cancer (117,118). However, Both KDM5A and KDM5B have 3 PHD domains, while KDM5C and KDM5D have only 2 PHD domains. Since the PHD domain is important for the binding of H3K4 with the JmjC domain, KDM5C and KDM5D may exhibit poor catalytic function and different effects in cancer compared to KDM5A and KDM5B (29).
Compared to normal tissues, KDM5A is overexpressed in cancer tissues and contributes to tumor growth and poor prognosis. KDM5A has the ability to repress p27, a cyclin-dependent kinase (CDK) inhibitor in cancer, trigger G1/S phase transition and promote tumor malignancy (119–122). Furthermore, by demethylating H3K4me2/me3 at the promoter, KDM5A was able to suppress the expression of insulin-like growth factor 2 mRNA binding protein 2 and NOTCH2, facilitating tumor proliferation, invasion and metastasis (123,124).
KDM5B mainly has oncogenic effects in cancers. In breast cancer, KDM5B was indicated to be overexpressed and associated with poor prognosis (125). Furthermore, it was indicated that KDM5B suppressed BRCA1, caveolin 1 and homeobox A5 expression by reducing H3K4me3 levels and facilitated G1 progression and tumor growth in breast cell lines (126). Through activating the c-Met signaling pathway or inhibiting p53 accumulation, KDM5B promoted lung cancer cell aggressiveness (127,128). In addition, other studies also indicated that knockdown of KDM5B led to cell cycle arrest at the G1/S phase; the ability of KDM5B to influence tumor proliferation by adjusting the cell cycle was identified in liver cancer, bladder cancer and acute lymphoblastic leukemia (129–131). Furthermore, the oncogenic effect of KDM5B in prostate cancer and colorectal cancer by demethylating H3K4 was identified (132,133).
Unlike that of KDM5A and KDM5B, the role of KDM5C in tumors has remained elusive. In clear-cell renal cell carcinoma xenograft models, tumor cells highly expressing KDM5C were able to significantly suppress tumor growth (134). Furthermore, patients with renal cancer and KDM5C-inactivating mutations had shorter overall survival, suggesting the tumor-suppressive role of KDM5C (135,136). Of note, the tumor-suppressive effect of KDM5C was also observed in intrahepatic cholangiocarcinoma (137). However, KDM5C exhibits a tumor-promoting effect in other cancer types. In lung cancer, KDM5C facilitates tumor proliferation and metastasis by promoting H3K4me2 demethylation modification of the promoter of miR-133a and downregulation of miR-133a (138). Furthermore, KDM5C highly expressed in liver cancer was indicated to be associated with distant metastasis and poor prognosis by demethylating at H3K4 (139). In colon cancer, KDM5C was also observed to promote cell proliferation by demethylating H3K4me2/me3 (140). In addition, KDM5C upregulated ER expression and inhibited type I IFN expression in a breast cancer cell line, and, as a result, promoting breast carcinogenesis and cancer cell growth in a demethylase-independent manner (141).
KDM5D was mainly observed to have a tumor-suppressive effect. Upon specific knockdown of KDM5D, tumor cell apoptosis was reduced and tumor proliferation was promoted in a prostate cancer cell line (142). In addition, KDM5D repressed the invasion-associated genes matrix metallopeptidase 1 (MMP1), MMP2, MMP3 and MMP7 by demethylating H3K4me3, thus suppressing prostate cancer invasion and metastasis (143). Apart from prostate cancer, the mechanism of KDM5D to inhibit cancer cell growth and contributing to a better prognosis through its demethylating activity was also observed in gastric cancer and lung cancer (144–146).
KDM6 family and cancer
KDM6A (also named UTX), KDM6B (also named JMJD3) and KDM6C (also named UTY) belong to the KDM6 family. KDM6A is located at the X chromosome, KDM6C is located at the Y chromosome and KDM6B is located at chromosome 17 (147,148). All three contain the JmjC domain and have the ability to catalyze the demethylation of H3K27me2/me3 (147,149), although KDM6C has relatively poor catalytic activity compared to KDM6A and KDM6B (148).
Current evidence suggests both tumor-promoting and tumor-suppressive effects of KDM6A and KDM6B in cancers. KDM6A mutations frequently occur in various cancers. In hepatocellular carcinoma, overexpression of KDM6A significantly suppressed tumorigenesis (150). In addition, by inhibiting enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)-mediated transcriptional repression through catalyzing demethylation of H3K27me3, KDM6A acts as a tumor suppressor in bladder cancer (151). However, a recent study identified the oncogenic role of KDM6A and KDM6B by epigenetically targeting stemness-controlling genes through demethylating H3K27me3, which makes KDM6A and KDM6B important in maintaining cancer cell stemness. At the same time, upregulation of KDM6B was indicated to be strongly associated with a higher recurrence rate and shorter survival in colorectal cancer (152). Furthermore, significantly increasing the levels of H3K27me3 using GSK-J4, a KDM6 family inhibitor, suppressed tumor growth in lung cancer mouse models, indicating an oncogenic effect of KDM6A and KDM6B (153).
KDM7 family and cancer
The KDM7 family is composed of KDM7A (also named JHDM1D), KDM7B (also named PHF8) and KDM7C (also named PHF2). All demethylases of the KDM7 family share the same composition, containing a JmjC domain at the C-terminus and a PHD domain at the N-terminus. The PHD domain binds to H3K4me3, while the JmjC domain is responsible for binding to H3K9me2 (154). However, the structure of each demethylase is slightly different, which may be the reason for the different functions. Among the KDM7 family, KDM7C only catalyzes H3K9me2 demethylation. However, KDM7A and KDM7B are able to catalyze demethylation of H3K9me1/me2, H3K27 me1/me2 and H4K20me1 (155).
An early study demonstrated that KDM7A acts as a tumor suppressor by inhibiting the in vivo growth of B16 and HeLa cells upon overexpression of KDM7A, even though this suppressive effect was not prominent in vitro (156). However, recent studies have discovered the oncogenic role of KDM7A, since KDM7A was indicated to be upregulated in prostate cancer tissue (157) and to promote the migration and invasion of breast cancer cells in vitro and in vivo (158). Therefore, the definitive role of KDM7A remains to be determined.
By contrast, KDM7B was indicated to have an oncogenic effect. KDM7B was determined to be associated with a higher Gleason score and poor prognosis by comparing prostate cancer tissue samples from 97 patients (159). In addition, KDM7B was indicated to act as an oncogene by activating genes related to tumor progression [PRKCA, ICAM-1, Snail (SNAI1), VIM and FIP200] in a demethylase-dependent or demethylase-independent manner and promote tumor progression in gastric cancer and hepatocellular carcinoma (160–162). However, its demethylase-catalyzing ability is also responsible for other effects. By catalyzing demethylation of H3K4me3 and H3K9me2/1, KDM7B activates the expression of SNAI1, which contributed to breast cancer epithelial-to-mesenchymal transition, tumorigenesis and metastasis (163). In addition to SNAI1, forkhead box protein A2 was also epigenetically upregulated by KDM7B through demethylating H3K9me1/me2, H3K27me2 and H4K20me1, further illustrating the oncogenic effect of KDM7B (164).
By contrast, KDM7C acts as a tumor suppressor. KDM7C expression was indicated to be downregulated in hepatocellular, colon and stomach cancer tissues as compared with that in normal tissues. Upregulation of KDM7C was associated with a favorable prognosis in hepatocellular carcinoma and decreased tumor cell migration (165). Another study demonstrated that KDM7C demethylates H3K9me2 at p53 promoters, resulting in activation of p53 transcription and suppression of tumor growth (166).
KDM8 family and cancer
KDM8 (also named JMJD5) has a JmjC domain and β-barrel fold structure and has H3K36me2 demethylating activity (167). However, the effect of KDM8 in tumorigenesis has remained to be determined. In an early study, KDM8 was indicated to be overexpressed in breast cancer tissues, catalyzing H3K36me2 demethylation and leading to cyclin A1 overexpression. This results in the initiation of G2/M phase transition and the promotion of tumor cell proliferation (168). In addition, downregulation of KDM8 was indicated to inhibit tumor proliferation and metastasis in oral cancer by upregulating the expression of p53 and E-cadherin and downregulating the expression of N-cadherin and vimentin (169). However, in a large-scale, multi-cohort study of gene expression profiles in several cancer types, KDM8 was indicated to be downregulated in pancreatic cancer and liver cancer, and was reduced as the tumor grade increased. Furthermore, the expression of KDM8 was negatively correlated with the hypoxia score and the expression of cell cycle genes (such as CCNA2, CCNB1, CDK1 and CDK2), indicating the tumor-suppressive role of KDM8 (170). Therefore, further studies on KDM8 are warranted.