acy-1215 and Triple-Negative-Breast-Neoplasms

Mutations of p53 tumor suppressors occur more frequently in cancers at advanced stages or in more malignant cancer subtypes such as triple‑negative breast cancer. Thus, restoration of p53 tumor suppressor function constitutes a valuable cancer therapeutic strategy. In the present study, it was revealed that a specific inhibitor of histone deacetylase 6, ACY‑1215, caused increased acetylation of p53 in breast cancer cells with mutated p53, which was accompanied by increased expression of p21. These results suggested that ACY‑1215 may lead to enhanced transcriptional activity of p53. It was also determined that ACY‑1215 treatment resulted in G1 cell cycle arrest and apoptosis in these cancer cells. Furthermore, ACY‑1215 displayed a synergistic effect with specific inhibitors of ATM, an activator of Akt, in inducing cancer cell apoptosis and inhibiting their motility. More importantly, it was observed that combination of ACY‑1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY‑1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.

Topics: Animals; Antineoplastic Agents; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Therapy, Combination; G1 Phase Cell Cycle Checkpoints; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Mammary Neoplasms, Experimental; Mice; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53

Progression of triple-negative breast cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast cancer metastasis, we performed RNA sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.

Topics: Acetylation; Animals; Cell Movement; Cell Proliferation; Disease Models, Animal; Exome Sequencing; Gene Expression Regulation, Neoplastic; Heterografts; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Mice; Microtubule Proteins; Neoplasm Metastasis; Pyrimidines; Sequence Analysis, RNA; Triple Negative Breast Neoplasms; Tubulin