Novel coronavirus disease 2019 (COVID-19) severity is highly variable, with pediatric patients typically experiencing less severe infection than adults and especially the elderly. The basis for this difference is unclear. We find that mRNA and protein expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, increases with advancing age in distal lung epithelial cells. However, in humans, ACE2 expression exhibits high levels of intra- and interindividual heterogeneity. Further, cells infected with SARS-CoV-2 experience endoplasmic reticulum stress, triggering an unfolded protein response and caspase-mediated apoptosis, a natural host defense system that halts virion production. Apoptosis of infected cells can be selectively induced by treatment with apoptosis-modulating BH3 mimetic drugs. Notably, epithelial cells within young lungs and airways are more primed to undergo apoptosis than those in adults, which may naturally hinder virion production and support milder COVID-19 severity.
TGF-β1 is enriched in the tumor microenvironment and acts as a key inducer of epithelial to mesenchymal transition (EMT) in lung cancer. The NOTCH signaling pathway is conserved across species and is an essential pathway for development, cell differentiation, and cancer biology. Dysregulation of Notch signaling is a common feature of non-small cell lung cancer (NSCLC) and is correlated with poor prognosis. Crosstalk exists between the NOTCH and TGF-β signaling pathways in EMT. Herein we report that histone deacetylase 6 (HDAC6) modulates TGF-β1-mediated activation of the Notch pathway. HDAC6, a primarily cytoplasmic deacetylase, mediates TGF-β1-induced EMT in human lung cancer cells. Inhibition of HDAC6 with a small molecule inhibitor, namely tubacin or with siRNA attenuated TGF-β1-induced Notch-1 signaling. We show that TGFβ-1-induced EMT is accompanied by rapid HDAC6-dependent deacetylation of heat shock protein 90 (HSP90). Consistently, inhibition of HSP90 with its small molecule inhibitor 17AAG attenuated expression of TGF-β1-induced Notch-1 target genes, HEY-1 and HES-1. These findings reveal a novel function of HDAC6 in EMT via mediating the TGF-β-Notch signaling cascade, and support HDAC6 as a key regulator of TGFβ-induced EMT in NSCLC. This work suggests that HDAC6 may be an attractive therapeutic target against tumor progression and metastasis.
Angiotensin-converting enzyme 2 (ACE2) maintains cardiovascular and renal homeostasis but also serves as the entry receptor for the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), the causal agent of novel coronavirus disease 2019 (COVID-19). COVID-19 disease severity is typically lower in pediatric patients than adults (particularly the elderly), but higher rates of hospitalizations requiring intensive care are observed in infants than in older children - the reasons for these differences are unknown. ACE2 is expressed in several adult tissues and cells, including alveolar type 2 cells of the distal lung epithelium, but expression at other ages is largely unexplored. Here we show that ACE2 transcripts are expressed in the lung and trachea shortly after birth, downregulated during childhood, and again expressed at high levels in late adulthood. Notably, the repertoire of cells expressing ACE2 protein in the mouse lung and airways shifts during key phases of lung maturation. In particular, podoplanin-positive cells, which are likely alveolar type I cells responsible for gas exchange, express ACE2 only in advanced age. Similar patterns of expression were evident in analysis of human lung tissue from over 100 donors, along with extreme inter- and intra-individual heterogeneity in ACE2 protein expression in epithelial cells. Furthermore, we find that apoptosis, which is a natural host defense system against viral infection, is dynamically regulated during lung maturation, resulting in periods of heightened apoptotic priming and dependence on pro-survival BCL-2 family proteins including MCL-1. Infection of human lung cells with SARS-CoV-2 triggers an unfolded protein stress response and upregulation of the endogenous MCL-1 inhibitor Noxa; in young individuals, MCL-1 inhibition is sufficient to trigger apoptosis in lung epithelial cells and may thus limit virion production and inflammatory signaling. Overall, we identify strong and distinct correlates of COVID-19 disease severity across lifespan and advance our understanding of the regulation of ACE2 and cell death programs in the mammalian lung. Furthermore, our work provides the framework for translation of apoptosis modulating drugs as novel treatments for COVID-19.
Histone deacetylase 6 (HDAC6) regulates cytoplasmic signaling networks through deacetylation of various cytoplasmic substrates and serves as a key member of the ubiquitin proteasome system (UPS). This study is focused on HDAC6 regulation of the Notch1 receptor that plays a crucial role in tumor growth in NSCLC. A series of cell culture experiments were employed using A549, Lewis lung carcinoma 2 (LL2), and H1299 NSCLC cell lines to investigate HDAC6-mediated regulation of the Notch1 receptor through the UPS. HDAC6 was inhibited with small molecule inhibitors tubacin and ACY1215 in vitro and in vivo. Inhibition of HDAC6 led to reduced levels of Notch1 receptor in a dose-dependent manner in all three NSCLC cell lines tested. HDAC6 inhibition with ACY1215 led to G2 arrest, increased apoptosis, and increased levels of cleaved PARP1 in A549, LL2, and H1299 cell lines. In vivo inhibition of HDAC6 with ACY1215 significantly reduced LL2 tumor growth rate. Our data show that HDAC6 in NSCLC cells supports Notch1 signaling and promotes cell survival and proliferation. Our results support clinical investigation of HDAC6 inhibitors as a potential therapeutic option for treatment of NSCLC patients.
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