Programming and Regulation of Metabolic Homeostasis by HDAC11

Sun, Li; Evsikova, Caralina Marín de; Bian, Ka; Achille, Alexandra; Telles, Elphine; Pei, Huadong; Seto, Edward

doi:10.1016/j.ebiom.2018.06.025

Cited by 91 publications

(88 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While Sox2 might not be directly involved in the survival of differentiated cancer cells, its downstream targets like HK2 and PDK2 might be contributing in viability of the cells through their key roles in metabolic processes. Recently, HDAC11 has been also been shown to have role in metabolic homeostasis [55][56][57] . The ability of the tested compounds to downregulate the metabolic genes through HDAC11 and Sox2 might be a feature that will enable these inhibitors to eliminate stem-like and non-stem-like cancer cells simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

Bora-Singhal

Mohankumar

Saha

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) is known to have poor patient outcomes due to development of resistance to chemotherapy agents and the EGFR inhibitors, which results in recurrence of highly aggressive lung tumors. Even with recent success in immunotherapy using the checkpoint inhibitors, additional investigations are essential to identify novel therapeutic strategies for efficacious treatment for NSCLC. Our finding that high levels of histone deacetylase 11 (HDAC11) in human lung tumor tissues correlate with poor patient outcome and that depletion or inhibition of HDAC11 not only significantly reduces self-renewal of cancer stem cells (CSCs) from NSCLC but also decreases Sox2 expression that is essential for maintenance of CSCs, indicates that HDAC11 is a potential target to combat NSCLC. We find that HDAC11 suppresses Sox2 expression through the mediation of Gli1, the Hedgehog pathway transcription factor. In addition, we have used highly selective HDAC11 inhibitors that not only target stemness and adherence independent growth of lung cancer cells but these inhibitors could also efficiently ablate the growth of drug-insensitive stem-like cells as well as therapy resistant lung cancer cells. These inhibitors were found to be efficacious even in presence of cancer associated fibroblasts which have been shown to contribute in therapy resistance. Our study presents a novel role of HDAC11 in lung adenocarcinoma progression and the potential use of highly selective inhibitors of HDAC11 in combating lung cancers. Lung cancer is the leading cause of cancer related mortality in the US, with about 234,000 new cases expected to be diagnosed in 2018 and 154,000 deaths 1. Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer and has notably poor survival rates 2. Early stage NSCLC is treated by surgical resection, radiotherapy or chemotherapy. Chemotherapeutic agents like gemcitabine, platinum compounds and taxanes are widely used to treat both lung adenocarcinomas as well as squamous cell carcinomas, but the success rates vary significantly 3. NSCLC in smokers generally harbor mutations in the KRAS oncogene, while mutations in EGFR gene are prevalent in NSCLC in non-smokers. NSCLC has high mutational burden, and hence immunotherapy using checkpoint inhibitors is highly beneficial to a subset of the patients 4,5. Nevertheless, a significant number of NSCLC patients do not respond to immunotherapy; hence it is imperative to identify novel therapeutic strategies to combat this disease. This notion is further strengthened by the fact that there are no effective drugs that can target KRAS mutant lung cancers; furthermore, while there are highly potent tyrosine kinase inhibitors that target mutant EGFR, patients invariably develop resistance to these inhibitors resulting in recurrence of highly drug resistant metastatic tumors 6,7. It has been proposed that cancer stem cells (CSCs) contribute to tumor initiation, dormancy, recurrence and metastasis of various tumors, including NSCLC 8,9. It has been suggested ...

show abstract

Section: Discussionmentioning

confidence: 99%

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

Bora-Singhal

Mohankumar

Saha

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…More significantly, the knockout mice exhibited higher body temperature upon cold exposure, as well as higher UCP1 mRNA and protein expression levels in BAT in response to HFD treatment. Therefore, these data indicate that there was an overall enhancement of thermogenesis in the HDAC11 knockout mice (125).…”

Section: Hdac11mentioning

confidence: 58%

“…The lone member of class IV HDACs, HDAC11, was recently identified as a regulator of metabolic homeostasis (125). HDAC11-deficient mice were shown to be resistant to HFDinduced obesity and the metabolic syndrome (Figure 7A).…”

Section: Hdac11mentioning

confidence: 99%

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

et al. 2020

View full text Add to dashboard Cite

Over the past decade, the increasing prevalence of obesity and its associated metabolic disorders constitutes one of the most concerning healthcare issues for countries worldwide. In an effort to curb the increased mortality and morbidity derived from the obesity epidemic, various therapeutic strategies have been developed by researchers. In the recent years, advances in the field of adipocyte biology have revealed that the thermogenic adipose tissue holds great potential in ameliorating metabolic disorders. Additionally, epigenetic research has shed light on the effects of histone acetylation on adipogenesis and thermogenesis, thereby establishing the essential roles which histone acetyltransferases (HATs) and histone deacetylases (HDACs) play in metabolism and systemic energy homeostasis. In regard to the therapeutic potential of thermogenic adipocytes for the treatment of metabolic diseases, herein, we describe the current state of knowledge of the regulation of thermogenic adipocyte differentiation and adaptive thermogenesis through histone acetylation. Furthermore, we highlight how different HATs and HDACs maintain the epigenetic transcriptional network to mediate the pathogenesis of various metabolic comorbidities. Finally, we provide insights into recent advances of the potential therapeutic applications and development of HAT and HDAC inhibitors to alleviate these pathological conditions.

show abstract

“…Sun et al have demonstrated that knockout of HDAC11 in mice improved its resistance to metabolic syndrome and obesity by improving insulin sensitivity and glucose tolerance [ 60 ]. Studies by Bagchi et al also proved that the deletion of HDAC11 inhibited the HDAC11/BRD2 association, exacerbated brown adipose tissue formation, and enhanced insulin sensitivity HDAC11-KO mice when fed with a high-fat diet.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

et al. 2020

View full text Add to dashboard Cite

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein of the leucine zipper family, which mitigates inflammation and employs cytoprotective effects. Attempting to unravel the epigenetic regulation of type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU), we profiled the expression of eleven isoform-specific histone deacetylases (HDACs) and correlated them with NRF2 and cytokines. This study recruited a total of 60 subjects and categorized into DFU patients (n = 20), T2DM patients (n = 20), and healthy controls (n = 20). The DFU patients were subcategorized into uninfected and infected DFU (n = 10 each). We observed a progressive decline in the expression of NRF2 and its downstream targets among T2DM and DFU subjects. The inflammatory markers IL-6 and TNF-α were significantly upregulated, whereas anti-inflammatory marker IL-10 was significantly downregulated in DFU. Of note, a significant upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2,8, SIRT1, SIRT2, SIRT3, SIRT7 among DFU patients were observed. The significant positive correlation between NRF2 and SIRT1 in DFU patients suggested the vital role of NRF2/SIRT1 in redox homeostasis and angiogenesis. In contrast, the significant negative correlation between NRF2 and HDAC1, 3 and 4, implied an imbalance in NRF2-HDAC1, 3, 4 circuit. Furthermore, a significant positive correlation was observed between HDAC4 and IL-6, and the negative correlation between SIRT1 and IL-6 suggested the pro-inflammatory role of HDAC4 and the anti-inflammatory role of SIRT1 in NRF2 signaling. In conclusion, the epigenetic changes such as upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2, 8, SIRT1, SIRT2, SIRT6, SIRT7 and their association with NRF2 as well as inflammatory markers are suggestive of their roles in pathophysiology of T2DM and DFU.

show abstract

Programming and Regulation of Metabolic Homeostasis by HDAC11

Cited by 91 publications

References 45 publications

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

Contact Info

Product

Resources

About