C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Abstract

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

“…Furthermore, the transcriptional functions of both SP1 and KLF5 also depend on a posttranslational acetylation by p300, GCN5 or Tip60, through which SP1 or KLF5 acts as a transactivator or trans-suppressor, or converts the function from activator to suppressor, playing a critical role in pro-or antitumorigenesis. 31,32,50,51 In our study, we identified that direct deacetylation of both KLF5 and SP1 by HDAC4 is essential for MKK7 expression, while the increase in acetylated-SP1 and acetylated-KLF5 after HDAC4 inhibition switch to suppress MKK7 and glioma formation, highlighting a new mechanism that HDAC4 is crucial for SP1 and KLF5-mediated positive or negative regulation of MKK7 transcription.…”

Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases

“…We have also found that the overexpressed GDF15 protein in GDF15 Tg+/FVB mice (FVB background) inhibited the formation of urethane-induced lung tumors mediated by reduced lung inflammation via downregulation of the p38 MAPK signaling pathway, and induced apoptosis through the activation of caspase 3/7 (Cekanova, et al, 2009). In contrast, GDF15 has been reported to facilitate A549 cell proliferation via GCN5-dependent KLF5 acetylation (Zhao, et al, 2018). They reported an increase in GDF15 expression in the tumors based on immunohistochemistry, and decrease in tumor formation in A549 cells after silencing of GDF15 as examined by a xenograft tumor assay.…”

“…Baek and Eling Page 30 (Cekanova, et al, 2009) SPCA1 and H1299 cells Anti No A549 and H460 cells Anti No (Harn, et al, 2014) H460 cells Anti No (Kadara, Schroeder, Lotan, Pisano, & Lotan, 2006) A549 cells Pro No (Zhao, et al, 2018) Colorectal cancer HT29 and SW480 cells Pro Yes (C. HCT-116 cells Anti No (Baek, Kim, Nixon, Wilson, & Eling, 2001) GDF15 knock-out/MIN mouse Anti No (Zimmers, Gutierrez, & Koniaris, 2010) Azoxymethane-induced mouse model and MIN mouse model in GDF15 Tg mice Anti No Prostate Positive and Negative Health Effects of GDF15 observed in mice.…”

Advances in treatment of COVID-19

“…In an in vitro antiviral test, Lopinavir can inhibit SARS-CoV-induced pathological lesion [27]. In addition, clinical studies found that when SARS patients were treated with Lopinavir for 21 days, the diarrhea, resurgent fever and deteriorating chest imaging were markedly improved and virus load was markedly reduced [28]. At present, an open, randomized and controlled study concerning the effectiveness and safety of Lapinavir and Ritonavir for COVID-19 patients is being conducted.…”