MYST1/KAT8 contributes to tumor progression by activating EGFR signaling in glioblastoma cells

Abstract

With short survival time, glioblastoma (GBM) is the most malignant tumor in the central nervous system. Recently, epigenetic enzymes play essential roles in the regulation of tumorigenesis and cancer development of GBM. However, little is known about MYST1/KAT8/MOF, a histone acetylation enzyme, in GBM. The present study shows that MYST1 promotes GBM progression through activating epidermal growth factor receptor (EGFR) signaling. MYST1 expression was increased in GBM and was negatively correlated with prognosis in patients with glioma and GBM. Knockdown of MYST1 reduced cell proliferation and BrdU incorporation in LN229, U87, and A172 GBM cells. Besides, MYST1 downregulation also induced cell cycle arrest at G2M phase, as well as the reduced expression of CDK1, Cyclin A, Cyclin B1, and increased expression of p21CIP1/Waf1. Meanwhile, Self‐renewal capability in vitro and tumorigenecity in vivo were also impaired after MYST1 knockdown. Importantly, MYST1 expression was lowly expressed in mesenchymal subtype of GBM and was positively correlated with EGFR expression in a cohort from The Cancer Genome Atlas. Western blot subsequently confirmed that phosphorylation and activation of p‐Try1068 of EGFR, p‐Ser473 of AKT and p‐Thr202/Tyr204 of Erk1/2 were also decreased by MYST1 knockdown. Consistent with the results above, overexpression of MYST1 promoted GBM growth and activated EGFR signaling in vitro and in vivo. In addition, erlotinib, a US Food and Drug Administration approved cancer drug which targets EGFR, was able to rescue MYST1‐promoted cell proliferation and EGFR signaling pathway. Furthermore, the transcription of EGF, an EFGR ligand, was shown to be positively regulated by MYST1 possibly via H4K16 acetylation. Our findings elucidate MYST1 as a tumor promoter in GBM and an EGFR activator, and may be a potential drug target for GBM treatment.

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

“…Because lysine acetylation is mostly regulated by acetyltransferases and deacetylases, we used GPS-PAIL 2.0 software to make simple predictions for the seven acetyltransferases of the differentially acetylated proteins we quantified. Previous studies have shown that the down-regulation of acetyltransferase KAT3B induces apoptosis in renal carcinoma and the variations in the expression levels of MYSTI/MOF/KAT8 may affect the cell cycle and the EGFR signaling pathway ( Cocco et al, 2018 ; Dong et al, 2019 ). Additionally, our prediction results identified certain acetyltransferases with high scores, such as KAT8 which can act on Parp2 (K36/K51 site) and Casp3 (K25 site).…”

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

“…2 e), the hub genes from the green yellow and yellow modules were the most connected, such as Supt16 , Psen2 , Gyg , Hgsnat , Vat1 , Mapkapk3 (green yellow), and the genes Prelid1 , Snx3 , Ost4 , Mvb12b , Kat8 , Pla2g2a , and Ttyh2 (yellow), followed by hubs from the blue, midnight blue, and light cyan modules. Among these hub genes, Supt16 is a component of the FACT (facilitates chromatin transcription) complex, and Kat8 codes for a lysine acetyltransferase that acetylates H4K16; both of which are altered in aggressive tumors [ 23 , 24 ]. In the midnight blue module, the hub Flt1 (fms-related tyrosine kinase 1) is a VEGF receptor that participates in the proliferation of melanoma cells [ 25 ], whereas Cdh5 (VE-cadherin) is highly expressed in metastatic melanoma [ 26 ].…”

Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer

“…CSC phenotype [33] MOF (KAT8) Tumor promoter in GBM [34] AML, acute myeloid leukemia; AT-1/2, acetyl-CoA transporter 1/2; ATAT-1, alpha-tubulin Lysine acetylation can also be achieved in a non-enzymatic fashion (Figure 1), notably in the acetylation of calf thymus nuclear histone protein with acetyl-CoA, that is dependent on pH, period of incubation, ionic strength and ionic species [35]. Recent studies also suggested that, under basal conditions, "non-enzymatic lysine acetylation" is maintained at a very low stoichiometry in mitochondria [36,37].…”