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?-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration.

ABSTRACT: Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies that remain wanting. In this study, we report that elevated levels of ?-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high ?-tubulin acetylation levels that extended along microtentacle (McTN) protrusions. Mutation of the acetylation site on ?-tubulin and enzymatic modulation of this posttranslational modification exerted a significant impact on McTN frequency and the reattachment of suspended tumor cells. Reducing ?-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of more than 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared with primary tumors. Proteomic analysis of an independent cohort of more than 390 patient specimens further documented the relationship between increased ?-tubulin acetylation and the aggressive behaviors of basal-like breast cancers, with a trend toward increased risk of disease progression and death in patients with high-intensity ?-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated ?-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in patients with breast cancer.

SUBMITTER: Boggs AE

PROVIDER: S-EPMC4350791 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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α-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration.

Boggs Amanda E AE Vitolo Michele I MI Whipple Rebecca A RA Charpentier Monica S MS Goloubeva Olga G OG Ioffe Olga B OB Tuttle Kimberly C KC Slovic Jana J Lu Yiling Y Mills Gordon B GB Martin Stuart S SS

Cancer research 20141212 1

Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies that remain wanting. In this study, we report that elevated levels of α-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high α-tubulin acetylation levels that extended along microtentacle (McTN) protrusions. Mutation o ...[more]

PMID: 25503560

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Project description:Macroautophagy/autophagy, a fundamental process for degradation of macromolecules and organelles, occurs constitutively at a basal level and is upregulated in response to stress. Whether autophagy regulates protein acetylation and microtubule stability in vascular smooth muscle cells (VSMCs) migration, however, remains unknown. Here, we demonstrate that the histone acetyltransferase KAT2A/GCN5 (lysine acetyltransferase 2) binds directly to the autophagosome protein MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) via a conserved LC3-interacting region (LIR) domain. This interaction is required for KAT2A sequestration in autophagosomes and degradation by lysosomal acid hydrolases. Suppression of autophagy results in KAT2A accumulation. KAT2A functions as an acetyltransferase to increase TUBA/α-tubulin acetylation, promote microtubule polymerization and stability, ultimately inhibiting directional cell migration. Our findings indicate that deacetylation of TUBA and perturbation of microtubule stability via selective autophagic degradation of KAT2A are essential for autophagy-promoting VSMC migration. Abbreviations: ACTB: actin beta; ATAT1: alpha tubulin acetyltransferase 1; ATG: autophagy-related; BECN1: beclin 1; CQ: chloroquine; FBS: fetal bovine serum; GST: glutathione S-transferase; H4K16ac: histone H4 lysine 16 acetylation; HASMCs: human aortic smooth muscle cells; HBSS: Hank's buffered salt solution; HDAC6: histone deacetylase 6; hMOF: human males absent on the first; IP: immunoprecipitation; KAT2A/GCN5: lysine acetyltransferase 2A; Lacta: lactacystin; LIR: LC3-interaction region; MAP1LC3: microtubule associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTOC: microtubule-organizing center; PE: phosphatidylethanolamine; PtdIns3K: class III phosphatidylinositol 3-kinase; RUNX2: runt-related transcription factor 2; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; VSMCs: vascular smooth muscle cells; WT: wild-type.

Dataset Information

?-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration.

Publications

α-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration.

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