α-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 which 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 protrusions. Mutation of the acetylation site on α-tubulin and enzymatic modulation of this post-translational modification exerted a significant impact on microtentacle frequency and the re-attachment of suspended tumor cells. Reducing α-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of over 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared to primary tumors. Proteomic analysis of an independent cohort of over 390 patient specimens further documented the relationship between increased α-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 α-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated α-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in breast cancer patients.

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

“…Recently, high level of acetylated tubulin expression have been found correlated with a higher tumor grade in squamous cell carcinoma of the head and neck [57], and its expression has been suggested as a prognostic marker in epithelial malignancies and as a marker for sensitivity to chemotherapy [58]. A relationship between high level of α-tubulin acetylation and metastatic behaviour of basallike breast cancers, it has been also recently reported [59]. Hence, level of α-tubulin acetylation may represent a reliable biomarker for predicting response to HATi treatment to identify patients likely to benefit from these drugs.…”

Tubulin acetylation: responsible enzymes, biological functions and human diseases

“…This modification is a prognostic marker for squamous cell carcinoma of the head and neck [184]. Elevated tubulin acetylation in primary breast tumors is linked to the basal-like subtype of breast cancer and an increased risk of disease progression and death [185]. Mechanistically, elevated tubulin acetylation promotes adhesion and invasion of breast cancer cells [185].…”

“…Elevated tubulin acetylation in primary breast tumors is linked to the basal-like subtype of breast cancer and an increased risk of disease progression and death [185]. Mechanistically, elevated tubulin acetylation promotes adhesion and invasion of breast cancer cells [185]. Ectopic ATAT1 expression in cultured cells increases tubulin acetylation and enhances formation of microtentacles, which are membrane protrusions in detached breast cancer cells [185].…”

“…Mechanistically, elevated tubulin acetylation promotes adhesion and invasion of breast cancer cells [185]. Ectopic ATAT1 expression in cultured cells increases tubulin acetylation and enhances formation of microtentacles, which are membrane protrusions in detached breast cancer cells [185]. ATAT1 is also associated with pancreatic cancer-initiating cells [186].…”

Depletion of JMJD5 sensitizes tumor cells to microtubule-destabilizing agents by altering microtubule stability

“…3,4 The a-and b-tubulin subunits undergo various post-translational modifications, 5,6 and post-translational acetylation and detyrosination are commonly used as markers of microtubule stabilization. [7][8][9][10] Increased levels of microtubule acetylation and detyrosination have been observed in multiple types of cancer cells, [11][12][13][14][15] and both microtubule-stabilizing and microtubule-destabilizing agents have been widely used in cancer treatment. [16][17][18] However, the clinical applications of these agents have shown the emergence of drug-resistant tumor cells, due to the overexpression of different beta-tubulin isotypes, 19,20 or tubulin mutations.…”