HDAC1 is the prototypical human histone deacetylase (HDAC) enzyme responsible for catalyzing the removal of acetyl group from lysine residues on many substrate proteins. By deacetylating histones and non-histone proteins, HDAC1 has a profound effect on the regulation of gene transcription and many processes related to cell growth and cell death, including cell cycle progression, DNA repair, and apoptosis. Early studies reveal that, like most eukaryotic proteins, the functions and activities of HDAC1 are regulated by post-translational modifications. For example, serine phosphorylation of HDAC1 by protein kinase CK2 promotes HDAC1 deacetylase enzymatic activity and alters its interactions with proteins in corepressor complexes. Here, we describe an alternative signaling pathway by which HDAC1 activities are regulated. Specifically, we discover that EGFR activity promotes the tyrosine phosphorylation of HDAC1, which is necessary for its protein stability. A key EGFR phosphorylation site on HDAC1, Tyr72, mediates HDAC1’s anti-apoptotic function.
Fig: Phosphorylation of HDAC1 at Tyr72 is critical for the expression of HDAC1 protein: a Immunoprecipitation of endogenous HDAC1 and Western blot analysis to detect tyrosine phosphorylation in A549 and PC-9 cells with the indicated antibodies. b Predicted tyrosine phosphorylation sites in HDAC1 detected in non-small cell lung cancer cells. c Predicted tyrosine phosphorylation sites were mutated to the nonphosphorylatable phenylalanine (YF mutation). Plasmids were transiently transfected into HEK293T cells and their expression was detected by Western blot analysis. d Expression levels of Flag HDAC1 Y72F from several independent clones were assessed by Western blot. e HDAC1 WT and Y72F sequences were subcloned from the Flag-tag vector to an HA-tag vector. Plasmids were transiently transfected into HEK293T cells and their expression was detected by Western blot. f Flag HDAC1 plasmid was mutated at Tyr72 to alanine (A), glutamic acid (E), or phenylalanine (F). Plasmids were transiently transfected into HEK293T cells and their expression was detected by Western blot. g Flag HDAC1 Y72F mutant plasmid was mutated to express F72Y. Plasmids were transiently transfected into HEK293T cells and their expression was detected by Western blot.
Given that HDAC1 overexpression and EGFR activity are strongly related with tumor progression and cancer cell survival, HDAC1 tyrosine phosphorylation may present a possible target to manipulate HDAC1 protein levels in future potential cancer treatment strategies.
Bahl, S., Ling, H., Acharige, N.P.N. et al. EGFR phosphorylates HDAC1 to regulate its expression and anti-apoptotic function. Cell Death Dis12, 469 (2021). https://doi.org/10.1038/s41419-021-03697-6