Epigenetic regulation of gene expression is important for plant adaptation to environmental changes. Previous results showed that Arabidopsis RPD3-like histone deacetylase HDA9 is known to function in repressing plant response to stress in Arabidopsis. However, how HDA9 targets to specific chromatin loci and controls gene expression networks involved in plant response to stress remains largely unclear. Here, we show that HDA9 represses stress tolerance response by interacting with and regulating the DNA binding and transcriptional activity of WRKY53, which functions as a high-hierarchy positive regulator of stress response. We found that WRKY53 is post-translationally modified by lysine acetylation at multiple sites, some of which are removed by HDA9, resulting in inhibition of WRKY53 transcription activity. Conversely, WRKY53 negatively regulates HDA9 histone deacetylase activity. Collectively, our results indicate that HDA9 and WRK53 are reciprocal negative regulators of each other's activities, illustrating how the functional interplay between a chromatin regulator and a transcription factor regulates stress tolerance in plants.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by its highly aggressive behavior, early recurrence, and poor outcomes, when compared with other subtypes. Due to the absence of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, TNBC lacks meaningful biomarkers and an effective therapeutic strategy. Chemotherapy remains the main adjuvant treatment for patients with TNBC. Anthracycline/taxane-based regimens are the standard of care in adjuvant settings. The addition of capecitabine or platinum may offer extra benefits to patients with TNBC, but at the cost of increased toxicity or adverse events. Dose-dense chemotherapy may enhance treatment efficacy in patients who are able to tolerate the treatment regimen, especially in high-risk patients. As a heterogenous disease, TNBC can be classified into several molecular subtypes according to genomic or transcriptional features, which may indicate potential targets for more precise and individualized treatment strategies. With our increased understanding of signal pathways associated with TNBC, as well as the discovery of novel biomarkers indicative of TNBC prognosis, several new therapeutic options are under investigation, and some have already reported good results. In this review, we summarized the current conventional therapeutic strategies and emerging clinical trials regarding adjuvant treatment for TNBC. Furthermore, we evaluated the prognostic value of several potential targets and the progress of targeted therapy in TNBC, both in neoadjuvant and adjuvant settings. KEYWORDSTriple-negative breast cancer; adjuvant chemotherapy; targeted therapy; prognostic factors Adjuvant treatment for TNBCTNBC lacks ER, PR, and HER2 expression and responds poorly towards endocrine and anti-HER2 therapies. Chemotherapy is therefore the preferred treatment for TNBC patients in neoadjuvant, adjuvant, and metastatic settings according to numerous clinical guidelines (e.g., the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the European Society for Medical Oncology).There is no evidence yet to indicate that a specific chemotherapy

Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA‐seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.

Copy number alterations (CNAs) are pivotal genetic events in triple-negative breast cancer (TNBC). Here, our integrated copy number and transcriptome analysis of 302 TNBC patients reveals that gene alpha-endosulfine (ENSA) exhibits recurrent amplification at the 1q21.3 region and is highly expressed in TNBC. ENSA promotes tumor growth and indicates poor patient survival in TNBC. Mechanistically, we identify ENSA as an essential regulator of cholesterol biosynthesis in TNBC that upregulates the expression of sterol regulatory element-binding transcription factor 2 (SREBP2), a pivotal transcription factor in cholesterol biosynthesis. We confirm that ENSA can increase the level of p-STAT3 (Tyr705) and activated STAT3 binds to the promoter of SREBP2 to promote its transcription. Furthermore, we reveal the efficacy of STAT3 inhibitor Stattic in TNBC with high ENSA expression. In conclusion, the amplification of ENSA at the 1q21.3 region promotes TNBC progression and indicates sensitivity to STAT3 inhibitors.

Immune response and immunotherapy play important roles in triple-negative breast cancer (TNBC). However, it is difficult to judge whether cancer is “immune-inactivated” or “immune-activated” by the carcinoma itself. The immune reaction of the microenvironment or the host to the tumor might be more informative. We assumed that clinically enlarged but pathologically negative regional lymph nodes served as an indicator for early immune response to tumors. First, we identified women with pN0 breast cancer disease from the current Surveillance, Epidemiology, and End Results database, and we compared the cN1 patients of breast cancer-specific survival (BCSS) with cN0 patients. Then, we extracted total RNA from 36 paired large (defined as minimum diameter more than 15 mm in size) and small lymph nodes (defined as maximum diameter less than 5 mm in size) from 12 TNBC, 12 HER2-enriched, and 12 luminal-like patients and performed RNA sequencing to explore the gene expression and cellular landscape of large nodes compared to small ones. Among 692 women with pathologically confirmed node-negative disease, cN1 patients unexpectedly had a better BCSS compared with cN0 in TNBC (adjusted hazard ratio 0.148, 95% CI, 0.040–0.546, P = 0.004) but not in other subtypes. Further transcriptome sequencing of 12 paired enlarged and small negative nodes from TNBC patients revealed that increased immune activation signaling (e.g., interferon-gamma response pathways) and abundant immune cells (activated dendritic cells, CD4+ and CD8+ T-cells) were more frequently observed in enlarged nodes. Our data implied that early immune activation in regional lymph nodes in TNBC might affect survival.