Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity

Abstract

Histone deacetylase 6 (HDAC6), a class IIb HDAC, plays an important role in many biological and pathological processes. Previously, we found that ERK1, a downstream kinase in the MAPK signaling pathway, phosphorylates HDAC6, thereby increasing HDAC6-mediated deacetylation of α-tubulin. However, whether HDAC6 reciprocally modulates ERK1 activity is unknown. Here, we report that both ERK1 and 2 are acetylated and that HDAC6 promotes ERK1 activity via deacetylation. Briefly, we found that both ERK1 and 2 physically interact with HDAC6. Endogenous ERK1/2 acetylation levels increased upon treatment with a pan-HDAC inhibitor, an HDAC6-specific inhibitor or depletion of HDAC6, suggesting that HDAC6 deacetylates ERK1/2. We also noted that the acetyltransferases CBP and p300 both can acetylate ERK1/2. Acetylated ERK1 exhibits reduced enzymatic activity toward the transcription factor ELK1, a well-known ERK1 substrate. Furthermore, mass spectrometry analysis indicated Lys-72 as an acetylation site in the ERK1 N-terminus, adjacent to Lys-71, which binds to ATP, suggesting that acetylation status of Lys-72 may affect ERK1 ATP binding. Interestingly, an acetylation-mimicking ERK1 mutant (K72Q) exhibited less phosphorylation than the WT enzyme and a deacetylationmimicking mutant (K72R). Of note, the K72Q mutant displayed decreased enzymatic activity in an in vitro kinase assay and in a cellular luciferase assay compared with the WT and K72R mutant. Taken together, our findings suggest that HDAC6 stimulates ERK1 activity. Along with our previous report that ERK1 promotes HDAC6 activity, we propose that HDAC6 and ERK1 may form a positive feedforward loop, which might play a role in cancer.Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are the enzymes that regulate core histones and non-histone proteins by deacetylation and acetylation, respectively (1). HATs acetylate proteins via adding acetyl groups to lysine residues, while HDACs catalyze a reverse reaction by removing the acetyl group from lysine residues. Up to now, a total of 18 HDACs are identified in humans and grouped HDAC6 deacetylates ERK12 into four classes based on their sequence similarity to yeast orthologs (2). Class I HDACs are homologous to yeast reduced potassium dependency 3 (Rpd3) and include HDACs 1, 2, 3 and 8. Class II HDACs are homologous to yeast histone deacetylase 1 (HdaI) and are further divided into class IIa and class IIb. Class IIa contains HDACs 4, 5, 7 and 9, and class IIb includes HDACs 6 and 10. HDAC11 is the only member in class IV. The deacetylase activity of HDAC classes I, II and IV is zinc-dependent. Class III HDACs, also knowns as sirtuins, are homologous to yeast silent information regulator 2 (Sir2), and the deacetylase activity of this class is oxidized nicotinamide adenine dinucleotide (NAD + )-dependent. HDAC6 belongs to class IIb HDACs. Its structure is quite unique among all HDACs, in that it contains two functional deacetylase domains in tandem and a zinc finger domain in the C-terminus (2,3). HDAC6...

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“…HDAC6 is a class IIb HDAC, which is a key regulator in diversified biological and pathological processes [22]. HDAC6 has been proven to enhance the activity of ERK1/2 through deacetylation, as well as to regulate the oncogenic activity and nuclear localization of mutant K-Ras [22,32].…”

“…HDAC6 is a class IIb HDAC, which is a key regulator in diversified biological and pathological processes [22]. HDAC6 has been proven to enhance the activity of ERK1/2 through deacetylation, as well as to regulate the oncogenic activity and nuclear localization of mutant K-Ras [22,32]. In terms of cancers, HDAC6 has been regarded as a crucial target of drug development for the treatment of cancers due to its main contribution in oncogenic cell transformation, which is also associated with tumorigenesis and improved survival of cancers [33].…”

“…HDAC6 silence recovered H4K12ac expression and inhibited the carcinogenic role of Ras-ERK1/2 in MG-63 cells HDAC6 is an important deacetylase, which is involved in regulating numerous biological and pathologic processes [22]. In the next experiments, we explored the regulatory relationship between HDAC6 and H4K12ac as well as investigated the effect of HDAC6 on Ras-ERK1/2-mediated proliferation and migration in MG-63 cells.…”

The unraveling of substrate specificity of histone deacetylase 6 domains using acetylome peptide microarrays and peptide libraries

“…Recent insights into the role of HDAC6 in the human (patho)physiology have been significantly advanced by the identification of novel substrates of the enzyme (11)(12)(13)34). However, there is paucity of data mapping substrate specificity and the mechanism of substrate recognition by HDAC6 at the peptide level.…”

Histone deacetylase 6 promotes growth of glioblastoma through the MKK7/JNK/c‐Jun signaling pathway

“…The elevated MAPK phosphatase 1 (MKP1) by HDAC inhibitors was demonstrated to impair self‐renewal, induce differentiation of glioma stem cells and reduce tumorigenesis in vivo (Arrizabalaga et al, ). HDAC6 directly deacetylates ERK1 at lysine 72 for stimulating its activity, which plays an important role in carcinogenesis (Wu et al, ). In this study, we found that HDAC6 inhibition caused a reduction in JNK/c‐Jun activity, preceding its inhibitive effects on glioma growth and invasion.…”