HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. PLoS One 2012;7(11):e49418
Date
11/16/2012Pubmed ID
23152903Pubmed Central ID
PMC3496684DOI
10.1371/journal.pone.0049418Scopus ID
2-s2.0-84869008969 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
We present for the first time that histone deacetylase 6 (HDAC6) regulates EGFR degradation and trafficking along microtubules in Pkd1 mutant renal epithelial cells. HDAC6, the microtubule-associated α-tubulin deacetylase, demonstrates increased expression and activity in Pkd1 mutant mouse embryonic kidney cells. Targeting HDAC6 with a general HDAC inhibitor, trichostatin (TSA), or a specific HDAC6 inhibitor, tubacin, increased the acetylation of α-tubulin and downregulated the expression of EGFR in Pkd1 mutant renal epithelial cells. HDAC6 was co-localized with EGF induced endocytic EGFR and endosomes, respectively. Inhibition of the activity of HDAC6 accelerated the trafficking of EGFR from early endosomes to late endosomes along the microtubules. Without EGF stimulation EGFR was randomly distributed while after stimulation with EGF for 30 min, EGFR was accumulated around α-tubulin labeled microtubule bundles. These data suggested that the Pkd1 mutation induced upregulation of HDAC6 might act to slow the trafficking of EGFR from early endosomes to late endosomes along the microtubules for degradation through deacetylating α-tubulin. In addition, inhibition of HDAC activity decreased the phosphorylation of ERK1/2, the downstream target of EGFR axis, and normalized EGFR localization from apical to basolateral in Pkd1 knockout mouse kidneys. Thus, targeting HDAC6 to downregulate EGFR activity may provide a potential therapeutic approach to treat polycystic kidney disease.
Author List
Liu W, Fan LX, Zhou X, Sweeney WE Jr, Avner ED, Li XAuthor
Ellis D. Avner MD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnilidesAnimals
Endocytosis
Endosomes
Epidermal Growth Factor
Epithelial Cells
ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
HEK293 Cells
Histone Deacetylase 6
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Hydroxamic Acids
Kidney
Lysosomes
Mice
Microtubules
Nocodazole
Phosphorylation
Protein Transport
Proteolysis
RNA, Small Interfering
TRPP Cation Channels
Tubulin
Up-Regulation
