Implications of m6A methylation and microbiota interaction in non-small cell lung cancer: From basics to therapeutics

Abstract

N6-methyladenine (m6A) is one of the most common RNA epigenetic modifications in all higher eukaryotes. Increasing evidence demonstrated that m6A-related proteins, acted as oncogenes or tumor suppressors, are abnormally expressed in the cell lines and tissues of non-small cell lung cancer (NSCLC). In addition, lung as the special immune organ contacts with the outer environments and thereby inevitably suffers from different types of microbial pathogen attack. Those microbial pathogens affect the development, progression, and clinical outcomes of NSCLC via altering host m6A modification to disrupt pulmonary immune homeostasis and increase the susceptibility; conversely, host cells modulate m6A modification to repress bacterial colonization. Therefore, m6A harbors the potential to be the novel biomarkers and targets for predicting poor prognosis and chemotherapy sensitivity of patients with lung cancer. In this paper, we provided an overview of the biological properties of m6A-modifying enzymes, and the mechanistic links among lung microbiota, m6A modification and NSCLC. Although the flood of novel m6A-related inhibitors represents many dramatic improvements in NSCLC therapy, their efficacy and toxicity in NSCLC are explored to address these pivotal gaps in the field.

RNA modification: mechanisms and therapeutic targets

“…We have discussed the important roles RNA methylation, including m6A, m5C, m1A and m7G, played in the malignant biological behavior of tumors as well as other common disease models. Developing specific inhibitors against RNA methylation related proteins is of great clinical value [ 381 ].…”

Microbiota in cancer: molecular mechanisms and therapeutic interventions

“…As one of the epigenetic/epigenetic transcriptome modifications, m 6 A RNA methylation is closely associated with cancer development and progression 88 . In order to increase susceptibility, microbial pathogens can modify host m 6 A methylation, which in turn disrupts lung immune homeostasis and affects the genesis, progression, and clinical outcome of non‐small cell lung cancer (NSCLC) 89 . Downregulating the m 6 A methyltransferase in CRC cells and patient‐derived xenograft tissues are one way in which F. nucleatum promotes CRC invasiveness.…”

“… 88 In order to increase susceptibility, microbial pathogens can modify host m 6 A methylation, which in turn disrupts lung immune homeostasis and affects the genesis, progression, and clinical outcome of non‐small cell lung cancer (NSCLC). 89 Downregulating the m 6 A methyltransferase in CRC cells and patient‐derived xenograft tissues are one way in which F. nucleatum promotes CRC invasiveness. Mechanistically, F. nucleatum activates yes1‐associated transcriptional regulator signaling, which inhibits forkhead box D3, a transcription factor for methyltransferase‐like 3 (METTL3), and consequently reduces METTL3 transcription.…”

Targeting fat mass and obesity-associated protein mitigates human colorectal cancer growth in vitro and in a murine model

“…m6A modification is the methylation of the adenosine base at the nitrogen-6 position of mRNA and reversibly mediated by the methyltransferase ("writers" including METTL3, METTL14 and WTAP) (7)(8)(9), the demethylases ("erasers" including FTO and ALKBH5) (10,11) and binding proteins that preferentially recognized m6A methylated transcripts and trigger downstream pathways ("readers" including YTH, HNRNP and IGF2BP) (12)(13)(14). m6A RNA methylation is also regulated by intestinal bacteria, which is related to the progression of cancers (15,16). Especially, m6A modifications in CRC cells and patientderived xenograft markedly suppressed by Fucobacterium nucleatum via downregulation of METTL3, which enhances the colorectal metastasis (17).…”