How Phospho-HDAC6 Phase Separation Could Change the Game for Triple-Negative Breast Cancer Treatment

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    Our journey into studying phospho-HDAC6 and its impact on triple-negative breast cancer (TNBC) started quite unexpectedly. Our lab typically focuses on epigenetic regulation and we initially just wanted to see how HDAC6 levels differed across various breast cancer types. HDAC6 is a well-known class II histone deacetylase, involved in removing acetyl groups from both histone and non-histone proteins1. It's known to play a significant role in cancer development, including breast cancer2. For instance, about 30% of human breast cancers might benefit from treatments that inhibit HDAC63. One particular inhibitor, BAS-2, has been effective in slowing down the energy-producing pathways in TNBC cells4. Though HDAC6 is primarily found in the cytoplasm, contributing significantly to how cells manage misfolded proteins, its broader impacts continue to unfold6, 7.

   Unexpectedly, during our routine testing, we stumbled upon a fascinating finding: the overall levels of HDAC6 were consistent across all samples, yet there was a notable increase in its presence within the nuclei of TNBC cells. This unusual observation piqued our interest, as it seemed we had uncovered a hidden piece of the puzzle in understanding cancer's complexity. Driven by this discovery, we delved deeper and discovered that HDAC6 was not merely ending up in the nucleus by chance—it was actively being phosphorylated at Serine 22 specifically within the nuclei of these TNBC cells. This modification appeared to be a crucial signal, potentially explaining the aggressive nature of TNBC.

   Driven by our curiosity, we turned to super-resolution microscopy to closely examine clinical samples and assess whether phosphorylated Serine 22 HDAC6 protein showed signs of phase separation in TNBC. The images were revealing: TNBC samples consistently displayed numerous punctate aggregates, a feature notably absent in non-TNBC and adjacent healthy tissues. Further scrutiny confirmed that these aggregates were not arbitrary clusters, but rather organized structures indicative of liquid-liquid phase separation (LLPS) within the nuclei of TNBC cells.

   Digging deeper, we found that the phosphorylation at Serine 22 was responsible for triggering LLPS condensates. This specific modification occurs within the intrinsically disordered region of HDAC6 and is crucial for initiating LLPS exclusively in TNBC cells. Moreover, the process is further intensified when the protein 14-3-3θ interacts with phosphorylated HDAC6, enhancing the phase separation.

   Transitioning from discovery to potential treatments, we applied phase separation screening techniques to identify a promising compound: Nexturastat A. This compound effectively disrupts the phosphorylated HDAC6 condensates by blocking the interaction between HDAC6 and Importin β. It does this by preventing the phosphorylation of HDAC6 at S22, which is crucial for HDAC6’s transport through the nuclear pore complex into the nucleus. As a result of this disruption, Nexturastat A significantly alters chromatin architecture and the boundaries of topologically associating domains, essential for maintaining proper chromatin looping. These changes have led to notable tumor reduction in TNBC patient-derived xenograft models, showcasing Nexturastat A's potential as a transformative treatment for this aggressive cancer.

   This breakthrough highlights the critical role of phosphorylated HDAC6 in TNBC and showcases the potential of targeting protein phase separation to stop tumor growth. As we further explore the mechanisms of LLPS in cancer and continue to identify more precise inhibitors, we grow increasingly hopeful about developing targeted and effective treatments for those battling TNBC. Our research not only deepens our understanding of how abnormal LLPS condensates affect oncogenic gene expression but also opens exciting new pathways for creating specific anticancer therapies. This progress offers renewed hope in the challenging fight against one of the most formidable types of breast cancer.

References:

  1. Valenzuela-Fernández, A., Cabrero, J.R., Serrador, J.M. & Sánchez-Madrid, F. HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol 18, 291-297 (2008).
  2. Banik, D. et al. HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer. Cancer Res 80, 3649-3662 (2020).
  3. Zeleke, T.Z. et al. Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer. Nat Cancer 4, 257-275 (2023).
  4. Dowling, C.M. et al. Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer. Sci Adv 7 (2021).
  5. Pulya, S. et al. HDAC6 as privileged target in drug discovery: A perspective. Pharmacol Res 163, 105274 (2021).
  6. Kawaguchi, Y. et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727-738 (2003).
  7. Mazzetti, S. et al. Phospho-HDAC6 Gathers Into Protein Aggregates in Parkinson's Disease and Atypical Parkinsonisms. Front Neurosci 14, 624 (2020).

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Cancer Biology
Life Sciences > Biological Sciences > Cancer Biology
Cancer Epigenetics
Life Sciences > Biological Sciences > Cancer Biology > Cancer Genetics and Genomics > Cancer Epigenetics
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