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  4. Role of HDAC6-STAT3 in immunomodulatory pathways in Colorectal cancer cells
 
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Role of HDAC6-STAT3 in immunomodulatory pathways in Colorectal cancer cells
Dr. Farkas-Pool, Carlos 
Facultad de Medicina 
Dra. González-Pecchi, Valentina 
Facultad de Medicina 
Dr. Hepp-Castro, Matías 
Facultad de Medicina 
Armijo-Silva, Marisol
Facultad de Medicina 
Mardones-Molina, Constanza
Facultad de Medicina 
Rivas-Valdes, Fernando
Facultad de Medicina 
Salgado-Quintana, Katherine
Facultad de Medicina 
Navarrete-Munoz, C.
Villagra, A.
10.1016/j.molimm.2023.11.007
Elsevier
2023
Colorectal cancer (CRC) is one of the most common malignant neoplasms and the second leading cause of death from tumors worldwide. Therefore, there is a great need to study new therapeutical strategies, such as effective immunotherapies against these malignancies. Unfortunately, many CRC patients do not respond to current standard immunotherapies, making it necessary to search for adjuvant treatments. Histone deacetylase 6 (HDAC6) is involved in several processes, including immune response and tumor progression. Specifically, it has been observed that HDAC6 is required to activate the Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor involved in immunogenicity, by activating different genes in these pathways, such as PD-L1. Over-expression of immunosuppressive pathways in cancer cells deregulates T-cell activation. Therefore, we focused on the pharmacological inhibition of HDAC6 in CRC cells because of its potential as an adjuvant to avoid immunotolerance in immunotherapy. We investigated whether HDAC6 inhibitors (HDAC6is), such as Nexturastat A (NextA), affected STAT3 activation in CRC cells. First, we found that NextA is less cytotoxic than the non-selective HDACis panobinostat. Then, NextA modified STAT3 and decreased the mRNA and protein expression levels of PD-L1. Importantly, transcriptomic analysis showed that NextA treatment affected the expression of critical genes involved in immunomodulatory pathways in CRC malignancies. These results suggest that treatments with NextA reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulatory genes involved in the inflammatory and immune responses. Therefore, targeting HDAC6 may represent an interesting adjuvant strategy in combination with immunotherapy.
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