Histone Demethylation Pathway

Figure 1. Histone demethylation pathway.

Histone demethylation overview

Histone methylation modification is a reversible dynamic regulation process. Methylation and/or demethylation status is closely related to epigenetics, transcriptional regulation, and maintenance of genomic integrity. Abnormalities in histone methylation status directly or indirectly affect various physiological and pathological processes. Histone demethylases are known to include the lysine-specific demethylase (LSD) family and the JMJD family containing the Jmj C domain. The study found that both have a close relationship with the occurrence of tumors. Therefore, the treatment of cancer with histone demethylation as a target has become a hot research topic.

Histone demethylation family

Unlike the dynamically regulated acetylation and phosphorylation processes, histone methylation modifications have been considered irreversible for a long time. Until 2004, Professor Shi discovered the histone lysine-specific demethylase (LSD1) for the first time. The demethylase LSD1 first binds to the histone tail lysine methylation site. The substrate was catalyzed to remove the methyl group at the tail of histones, confirming the presence of demethylase, and confirming that methylation and demethylation of histones is also a dynamic regulation process. However, LSD1 belongs to the FAD-dependent amine oxidase superfamily and can only catalyze the monomethyl and bis-methyl substrates (ie, at least one proton at the catalytic site) and remove the methyl group. This is inconsistent with the prevalence of lysine trimethylation, so there may be other mechanisms for the demethylation of lysine trimethylation. In 2006, it was first demonstrated that a histone demethylase containing the JmjC domain was named JHDM1A (JmjC domain-containing histone demethylase 1 A). Subsequent research has found more than 30 proteins containing the JmjC domain, forming another major class of demethylases. The JMJD family has many types and catalytic substrates. It can be roughly classified into JmjC domain and JARID1, JHDM1, JHDM2, JHDM3, UTX, and PHF8 structures according to nucleotide sequence alignment. JmjN and JmjC are the characteristic domains of the N-terminus and C-terminus of the JMJD family members, respectively. Among them, the JmjN domain is involved in transcriptional regulation, and JmjC is involved in the enzyme active center that constitutes the JMJD family.

Histone demethylation pathway

  1. Histone demethylation pathway cascade
    We briefly describe the histone demethylation cascade. KDM5B, alias JARID1B (Jumonji/ARID domain-containing protein 1B), is a target gene for non-coding RNA miR-137 for the mammary gland, in the development and progression of demethylase in cancer. The high expression of miR-137 in cancer patients may affect the demethylation ability of KDM5B, leading to the occurrence of malignant tumors. KDM4C, alias JHDM3C, has reduced expression in breast cancer and exhibits significant tumor suppressive effects in normal breast tissue. PHF8 (PHD. finger protein 8) plays an important role in breast cancer cell migration and tumor growth and can up-regulate tumor-related gene expression and promote tumorigenesis. In women with a higher risk of breast cancer, elevated expression of histone-lysine N-methyltransferase (EZH2) increases ductal hyperplasia (DH) and ductal carcinoma in situ (DCIS) risk demethylation of H3K27 by JMJD3 can reduce EZH2 activity and reduce the risk of tumorigenesis. Numerous studies have shown an increase in the expression of H3K27 methyltransferase and an increase in the content of H3K27me3 in clinical specimens and cell lines of various tumors. In addition, some carcinogens such as cigarettes, cigarette smoke condensate (CSC) and arsenic can increase the gene expression of EZH2, thereby increasing H3K27 methylation and inhibiting the expression of multiple genes, which may also be carcinogenic. KDM2A, alias JHDM1A, is highly expressed in myoepithelial cells of normal breast tissue and ductal carcinoma in situ. As the tumor progresses and metastasizes, the progressive loss of myoepithelial cells leads to a decrease in KDM2A expression. Therefore, KDM2A can be used as a new marker for the progression of breast tumors, providing a reference for studying the development of breast cancer and the progression of ductal carcinoma in situ to invasive carcinoma. Similarly, JMJD5 is closely related to the development, invasion and metastasis of breast cancer, and is an independent and unfavorable biological marker for poor overall survival of breast cancer patients. Zhao et al. found that overexpression of JMJD5 promoted the activation of the zinc finger transcription factor snail gene, induced EMT to promote cell invasion, and down-regulation of JMJD5 expression by siRNA inhibited the invasion of MDA-MB-231 cells. There is a dynamic epigenetic regulation mechanism during breast cancer transformation. The breast cancer patients have a decreased level of histone H3K9me2/me3 and an increase in the expression of demethylase KDM3A. Hui et al found that elevated expression of miR-491-5p in estrogen receptor-positive breast cancer patients reduced KDM4B expression and was positively correlated with prognosis. Wade et al. showed that inhibition of KDM3A can reactivate p53 tumor suppressor gene and induce apoptosis of ER+ cells. Knockdown of KDM3A also inhibits the growth of breast cancer stem cells (BCSCs) and increases their sensitivity to chemotherapeutic drugs. Therefore, compounds that target KDM4B and/or KDM3A may be effective in the treatment of hormone-dependent breast cancer. The prostate is a male-specific androgen-dependent gonadal organ. The elevated expression of androgen receptor (AR) is one of the important causes of prostate cancer. As the degree of malignancy of prostate cancer increases, the expression of androgen receptors gradually decreases. The histone demethylase KDMs family is thought to be an important coactivator of the androgen receptor. KDM4A, KDM4B or KDM4C is overexpressed in prostate cancer and regulates the expression of transcriptional regulators such as androgen receptors, which are essential for the growth of prostate cancer cells. LSD1, JHDM2A, and JHDM3C can promote the demethylation of H3K9me1, H3K9me2, and H3K9me3 near androgen-induced target genes, thereby activating target genes and inducing prostate cancer. Among them, high expression of LSD-1 is an important predictor of prostate cancer progression and metastasis. Clinically, LSD-1 selective inhibitors are used to treat prostate cancer. The combination of AR antagonists targeting LSD1 is a promising future treatment for prostate cancer. The study found that KDM5D, also known as JARID1D, can specifically bind to the promoter of an invasive gene, inhibiting transcription and inhibiting tumor invasion. KDM5B is a demethylating enzyme of H3K4me3, which can activate the transcription of androgen receptor regulatory genes and reduce the occurrence and metastasis of prostate cancer by lowering the level of H3K4me3. The study found that KDM5B is significantly elevated in advanced and metastatic prostate cancer (mPCa) and is associated with a high degree of malignancy. KDM3A can regulate androgen receptor activity and promote the development of prostate cancer. Although its mechanism of action is still unclear, it is still considered as a novel prostate marker. Tumor recurrence and metastasis is the main cause of colon cancer death. In the study of the mechanism of colon cancer development, the histone demethylase family is a potential novel biomarker, which is of great significance for the diagnosis and prognosis evaluation of colon cancer patients. Many studies have confirmed that tumor invasion ability is positively correlated with histone demethylase LSD1, N-cadherin expression, and negatively correlated with E-cadherin expression.
  2. Pathway regulation
    HKDMs are involved in the development and resistance of many diseases and are important targets for epigenetic drug development. At present, more HKDMs inhibitors have been discovered, but most of them have shortcomings such as low activity and poor selectivity. Therefore, it is urgent to find more highly active and highly selective HKDMs enzyme inhibitors. These inhibitors can be used not only as small molecule probes to explore the biological functions of demethylases, but also as new drugs. With the continuous updating of the crystal structure database, the crystal structure of HKDMs is increasing, and new drug research methods will be more extensive. Structure-based drug design will help to find more lysine demethylase inhibitors. The development of high-efficiency, low-toxicity and high-selective HKDMs inhibitors is a new direction for future anti-tumor treatments, which will surely benefit human health. LSD1 is the first histone lysine-specific demethylase 1 (LSD1) discovered by the Harvard Medical School's Shiyang team in 2004. The group first confirmed that histone methylation is a dynamic equilibrium process. This finding provides a new way of thinking about the mechanism of action of protein modification and its corresponding drug research. LSD1 is a flavin adenine dinucleotide-dependent demethylase that removes the mono- and bis-methyl groups of H3K4 and H3K9, thereby regulating the interaction of histones with other proteins and affecting the activation of gene transcription. The substrate of LSD1, in addition to histone H3, also has P53, DNA methyltransferase 1, STAT3, E2F1 and MYPT1, etc., which have been modified by methylation to regulate the biological functions of the corresponding cells. Studies have reported that LSD1 binds to many transcription factors and regulates gene expression. LSD1 is highly expressed in a variety of cancer cells and cancer tissues, such as neuroblastoma, retinoblastoma, prostate cancer, breast cancer, lung cancer, and bladder cancer cells. In addition, RNAi-mediated knockout assays and LSD1 inhibition assays have shown that LSD1 enzymes are involved in the proliferation of cancer cells, primarily through regulation of pre-living gene expression and p53 gene transcriptional activity. Therefore, LSD1 has become a new target for epigenetic anti-tumor drugs, and high-activity LSD1 inhibitors can be used as potential anticancer drugs for the treatment of related cancers. The structural characteristics of JMJD histone demethylase have been extensively studied. The structure of the crystal structure has led to the clarification of its structure and binding mechanism. The Jumonji domain is its catalytic center. The enzyme active center has three conserved amino acids, two histidines (His) and one glutamic acid (Glu). The catalytic process depends on the participation of O2 and the specific demethylation mechanism. Based on the catalytic principle and mechanism of JMJD histone demethylase, combined with structure-based and substrate-based drug design methods, drug researchers have discovered a series of JMJD histones methylase inhibitor. JMJD histone demethylase (JMJD demethylase) inhibitor is an important substance against the lysine demethylation process, regulating epigenetic misregulation and genetic abnormalities induced by lysine demethylation. The important weapon of expression is expected to become a new type of drug for the treatment of epigenetic diseases. At present, according to the molecular structure and discovery principle, JMJD demethylase inhibitors are mainly divided into four categories: α-ketoglutarate analogs, pyridine (or pyrimidine)-based JMJD demethylation enzyme inhibitors, hydroxamic acid JMJD demethylase inhibitors, polyphenolic JMJD demethylase inhibitors, and others.
  3. Relationship with disease
    Studies have shown that the misregulation of histone lysine demethylases (HKDMs) is closely related to the development of many diseases, such as senile diseases, and tumors. In addition, recent studies have shown that HKDMs are also associated with drug resistance in cancer drugs. Therefore, HKDMs have become an important target for the development of new anti-tumor drugs and have attracted more and more attention. To date, more HKDMs inhibitors have been discovered.


  1. Hashizume R, Andor N, Ihara Y, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nature Medicine. 2014, 20(12):1394-6.
  2. Lu C, Ward P S, Kapoor G S, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012, 483(7390):474-8.
  3. Kamikawa YF, Donohoe M E. Histone Demethylation Maintains Prdm14 and Tsix Expression and Represses Xist in Embryonic Stem Cells. Plos One. 2015, 10(5)e0125626.
  4. Wang A H, Zare H, Mousavi K, et al. The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis. Embo Journal. 2013, 32(8):1075-1086.

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