Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer

Abstract

Cancer stem-like cells (CSCs) have been proposed as a key driving force of tumor growth and relapse in colorectal cancer (CRC), and therefore, they are promising targets for cancer therapy. Epidemiological evidence has suggested that the daily use of aspirin reduces overall mortality of CRC and the risk of distant metastasis. We investigated the effect and mechanism of aspirin on CSCs in CRC.Methods: The ratio of CSCs was analyzed after aspirin treatment both in a cell model and patient samples. Chemically modified aspirin and immunoprecipitation were adopted to detect the target proteins of aspirin. A locus-specific light-inducible epigenetic modification system based on CRISPR technology was constructed to verify the causal relationship in these molecular events. In vivo characterization was performed in a xenograft model.Results: We found that aspirin induces apoptosis in enriched colorectal CSCs, inhibits tumor progression, and enhances the anti-neoplastic effects of chemotherapeutic agents. Furthermore, aspirin directly interacts with p300 in the nucleus, promotes H3K9 acetylation, activates FasL expression, and induces apoptosis in colorectal CSCs. Notably, these effects of aspirin are absent in non-CSCs since H3K9 is hypermethylated in non-CSCs and the effects are not induced by other NSAIDs. In addition, aspirin can suppress oxaliplatin-enriched CSCs and serve as an adjuvant therapy.Conclusions: Taken together, we revealed a unique epigenetic and cox-independent pathway (p300-AcH3K9-FasL axis) by which aspirin eliminates colorectal CSCs. These findings establish an innovative framework of the therapeutic significance of aspirin.

Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction

“…Once the tumors reached a size of approximately 50 mm 3 (within 5–7 days), the mice were randomly assigned to one of four groups (5 mice/group). Based on other prior studies, the mice were given osimertinib (5 mg/kg), aspirin (20 mg·kg −1 ), and a combination of osimertinib and aspirin by means of intragastric administration (Chen et al , 2018; Shi et al , 2017). The tumor volume was calculated as (length × width 2 )/2 and measured twice per week.…”

Aspirin mediates histone methylation that inhibits inflammation-related stemness gene expression to diminish cancer stemness via COX-independent manner

“…Previous studies attribute the anti-cancer potential of aspirin to the inhibition of cyclooxygenase-2 (COX-2) which is upregulated in various cancer cells [14,15]. Of note, an increasing body of evidence suggests that aspirin exhibits anti-cancer effects in a COX-independent manner [16].…”

“…Histone demethylases (HDMs) and histone deacetylases (HDACs) are the key enzymes that remove methyl and acetyl groups respectively to regulate gene transcription. In this regard, aspirin was reported to affect HDACs expression and suppress progression of some cancers like aspirin mediates H3K27 acetylation to prevent colon carcinogenesis and aspirin cooperates with p300 to activate H3K9 acetylation further to promote colorectal cancer cell apoptosis [16,21,22]. However, the specific roles and mechanisms of aspirin-mediated histone methylation in cancer stemness remains insufficient.…”

Aspirin inhibits cancer stem cells properties and growth of glioblastoma multiforme through Rb1 pathway modulation

“…According to the Cox-dependent hypothesis, the inhibition of this enzyme leads to decreased inflammation and, hence, decreased incidence in cancer. However, it is now clear that other pathways and multiple molecular mechanisms, aside Cox inhibition, may also play a role in aspirin's chemopreventive and anticancer properties(Hua, Zhang, Kong, Wang, & Jiang, 2018) including induction of apoptosis and chemotherapeutics sensibility, inhibition of proliferation, and metastasis (Z Chen, Li, et al, 2018;Kim et al, 2009;McCarty & Block, 2006;Pathi et al, 2012;X. Zhang, Feng, Li, Guo, & Li, 2018)…”