Lysine acetyltransferase 2B (KAT2B), also known as PCAF (P300/CBP associated factor), is the most common histone acclytransferase (HAT) in cells. KAT2B is highly expressed in epithelial tissues, endothelial tissues and muscle. KAT2B is involved in the transcriptional regulation of genes by acetylation of histones and non-histones. KAT2B can acetylate lysine residues (Lys) at specific sites of histones. Histone acetylation reduces its affinity to the DNA strand and relaxes the nucleosome structure, thus promoting the binding of DNA strands and transcriptional regulators, leading more conducive to gene transcription. KAT2B can form a complex with P300/CBP with acetyltransferase activity, which can both acetylate nucleosome histones and acetylate free histones. In addition, KAT2B also causes cell cycle arrest. Some reports have shown that KAT2B regulates histone and non-histone to regulate the expression level of the corresponding target genes. It has a certain relationship with the development of breast cancer, liver cancer, gastric cancer, ovarian cancer and esophageal squamous cell carcinoma.
KAT2B and tumor suppressor protein P53
Tumor suppressor protein P53 causes a series of physiological functions such as DNA damage repair, cell cycle and apoptosis when the body is stimulated. Acetylation plays an important regulatory role in P53 transcriptional activity. It has been shown that KAT2B acetylates Lys-320. When the tissue is under hypoxia, KAT2B will only decrease the degree of acetylation of Lys-382 of P53, thus P53 cannot be recruited on the promoter of the apoptotic gene BID, the BID gene cannot be regulated. At the same time, KAT2B regulates the activity of P53 to balance cell cycle arrest and apoptosis. In addition, KAT2B is also a coactivator of the tumor suppressor gene P53. KAT2B is capable of acetylating and modifying histones to promote binding of P53 to a target gene promoter and to regulate transcription of a target gene.
KAT2B and breast cancer
Some reports showed that Histone deacetylase (HDAC) is involved in the transcriptional expression of Estrogen receptor (ER), resulting in inhibition of ER gene transcription and down-regulation. HAT and HDAC are functionally antagonistic.KAT2B can promote transcription with multiple steroid nuclear receptors, such as formate receptors and glucocorticoid receptors. Studies have shown that β-estradiol (17β-estradiol, 17β-E 2), which is the main form of intracellular estrogen, promotes the expression of KAT2B protein and gene in MCF-7 cells, suggesting that estrogen can promote KAT2B protein and gene expression, enhances ER activity and forms a positive feedback mechanism for estrogen effects. Other studies have shown that the expression of KAT2B protein in cells is significantly decreased after PD98059 inhibits ERK signaling pathway, suggesting that 17β-E 2 can increase KAT2B protein expression by activating ERK signaling pathway, thus enhancing ER activity and enhancing positive feedback of estrogen effect. In addition, activated ERK promotes SRC-1 activation in vascular smooth muscle cells, and activated SRC-1 forms a complex with KAT2B to promote receptor gene transcription. In human breast cancer cells MCF-7, activated ERK can increase the sensitivity of estrogen receptor-positive breast cancer to estrogen by promoting KAT2B protein expression and enhancing estrogen receptor activity.
KAT2B and liver cancer
Hepatocellular carcinoma (HCC) is the most common hepatic malignant tumor with high malignancy. It lacks obvious clinical symptoms in the early stage. The high incidence and metastasis rate lead to poor therapeutic effect and poor prognosis. The expression of KAT2B in HCC is significantly lower than in normal tissues, this suggests that a decrease in KAT2B expression may be associated with HCC carcinogenesis. In addition, it has been found that the expression of KAT2B in HCC is inversely associated with tumor metastasis and tumor TNM staging, suggesting that KAT2B may inhibit tumor growth and metastasis. Moreover, KAT2B can acetylate and modify non-histone proteins such as Smad, cMyc, and P53 proteins, thus participate in pathophysiological processes in which cell division and proliferation, apoptosis, and DNA damage repair are closely related to tumors.
KAT2B and esophageal cancer
Esophageal cancer is one of the most common cancers in the world. The most common type of esophageal cancer is esophageal squamous cell carcinoma (ESCC), which is characterized by high mortality and variability in the diseased area. The development of esophageal squamous cell carcinoma is associated with the abnormal expression of proto-oncogenes and tumor suppressor genes. Some studies showed that KAT2B may be located in a tumor suppressor gene in the 3P24 region where deletions occur frequently. This means that KAT2B expression was significantly inhibited in many esophageal squamous carcinoma cell lines and primary esophageal squamous cell carcinoma samples, and it was located in the KAT2B gene promoter in addition to allelic deletions. Furthermore, both in vitro and in vivo results demonstrate that KAT2B inhibits tumor formation and inhibits cell growth. The mechanism is to down-regulate the expression of CDK2, up-regulate the expression of p53,p21waf1/cip1, Smad4, Rb, p27kip1 and Cyclin D1, thereby inhibiting the cell transition from G1 to S phase, suggesting that KAT2B is required for cell growth in esophageal squamous cell carcinoma.
KAT2B and Pancreatic Beta Cell
Some reports showed that loss of KAT2B induces defects in insulin secretion and glucose intolerance. In fact, KAT2B expression is defective in T2D islets, unfolded protein response (UPRer) signaling, the endoplasmic reticulum (ER) stress response and b cell function. They are closely related during metabolic stress. By regulating UPRer signaling pathways, KAT2B can be considered a critical transcriptional regulator of bcell function, especially after metabolic stress (Figure 1). The decrease of KAT2B expression in T2D islets and the inverse correlation with HbA1C levels further suggest a potential role for KAT2Bduring the onset of T2D. KAT2B contributes to the maintenance of efficient UPRer levels in b cells to ensure an efficient adaptive response to stressful conditions, such as those inflicted by obesity and metabolic stress.
Figure 1. A schematic model summarizing the role of KAT2B in Cells during obesity and metabolic stress and its role in UPRer regulation.
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