RESUMEN
Modulation of estrogen receptor (ER) and progesterone receptor (PR) expression, as well as their emerging functional crosstalk, remains a potential approach for enhancing the response to hormonal therapy in breast cancer. Aberrant epigenetic alterations induced by histone deacetylases (HDACs) were massively implicated in dysregulating the function of hormone receptors in breast cancer. Although much is known about the regulation of ER signaling by HDAC, the precise role of HDAC in modulating the expression of PR and its impact on the outcomes of hormonal therapy is poorly defined. Here, we demonstrate the involvement of HDAC6 in regulating PR expression in breast cancer cells. The correlation between HDAC6 and hormone receptors was investigated in patients' tissues by immunohistochemistry (n = 80) and publicly available data (n = 3260) from breast cancer patients. We explored the effect of modulating the expression of HDAC6 as well as its catalytic inhibition on the level of hormone receptors by a variety of molecular analyses, including Western blot, immunofluorescence, Real-time PCR, RNA-seq analysis and chromatin immunoprecipitation. Based on our in-silico and immunohistochemistry analyses, HDAC6 levels were negatively correlated with PR status in breast cancer tissues. The downregulation of HDAC6 enhanced the expression of PR-B in hormone receptor-positive and triple-negative breast cancer (TNBC) cells. The selective targeting of HDAC6 by tubacin resulted in the enrichment of the H3K9 acetylation mark at the PGR-B gene promoter region and enhanced the expression of PR-B. Additionally, transcriptomic analysis of tubacin-treated cells revealed enhanced activity of acetyltransferase and growth factor signaling pathways, along with the enrichment of transcription factors involved in the transcriptional activity of ER, underscoring the crucial role of HDAC6 in regulating hormone receptors. Notably, the addition of HDAC6 inhibitor potentiated the effects of anti-ER and anti-PR drugs mainly in TNBC cells. Together, these data highlight the role of HDAC6 in regulating PR expression and provide a promising therapeutic approach for boosting breast cancer sensitivity to hormonal therapy.
RESUMEN
Throughout the process of carcinogenesis, cancer cells develop intricate networks to adapt to a variety of stressful conditions including DNA damage, nutrient deprivation, and hypoxia. These molecular networks encounter genomic instability and mutations coupled with changes in the gene expression programs due to genetic and epigenetic alterations. Histone deacetylases (HDACs) are important modulators of the epigenetic constitution of cancer cells. It has become increasingly known that HDACs have the capacity to regulate various cellular systems through the deacetylation of histone and bounteous nonhistone proteins that are rooted in complex pathways in cancer cells to evade death pathways and immune surveillance. Elucidation of the signaling pathways involved in the adaptive responses to cellular stress and the role of HDACs may lead to the development of novel therapeutic agents. In this article, we overview the dominant stress types including metabolic, oxidative, genotoxic, and proteotoxic stress imposed on cancer cells in the context of HDACs, which guide stress adaptation responses. Next, we expose a closer view on the therapeutic interventions and clinical trials that involve HDACs inhibitors, in addition to highlighting the impact of using HDAC inhibitors in combination with stress-inducing agents for the management of cancer and to overcome the resistance to current cancer therapy.