N⁶-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

Purpose: Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC).

Hypoxia occurs not only in natural environments including high altitude, underground burrows and deep sea, but also in human pathological conditions, such as hypoxic solid tumors. It has been well documented that hypoxia related signaling pathway is associated with a poor clinical outcome. Our group has recently identified multiple novel genes critical for solid tumor growth comparing the genome-wide convergent/parallel sequence evolution of highland mammals. Among them, a single mutation on the retinol saturase gene (RETSAT) containing amino acid switch from glutamine (Q) to arginine (R) at the position 247 was identified. Here, we demonstrate that RETSAT is mostly downregulated in multiple types of human cancers, whose lower expression correlates with worse clinical outcome. We show that higher expression of RETSAT is positively associated with immune infiltration in different human cancers. Furthermore, we identify that the promoter region ofRETSATis highly methylated, which leads to its decreased expressions in tumor tissues comparing to normal tissues. Furthermore, we show that RETSAT knockdown promotes, while its overexpression inhibits, the cell proliferation ability of mouse embryonic fibroblasts (MEFs) and B16in vitro. In addition, the mice carrying homozygous Q247R mutation (RETSATR/R) is more resistant to xenograft tumor formation, as well as DMBA/TPA induced cutaneous keratinocyte carcinoma formation, compared to littermate wild-type (RETSATQ/Q) mice. Mechanistic study uncovers that the oncogenic factor, the prolyl isomerase (PPIase) Pin1 and its related downstream signaling pathway, were both markedly repressed in the mutant mice compared to the wild-type mice. In summary, these results suggest that interdisciplinary study between evolution and tumor biology can facilitate identification of novel molecular events essential for hypoxic solid tumor growth in the future.

Lung cancer has a high mortality rate worldwide. Non-SMC condensin I complex subunit H (NCAPH) has been identified to be one of the regulatory subunits of the condensin I complex, which is essential for the correct packaging and segregation of chromosomes in eukaryotes. NCAPH is abnormally overexpressed in various types of cancer. A pro-survival member of the Bcl-2 family, myeloid cell leukemia sequence 1 (Mcl-1) is also frequently overexpressed in multiple cancers and is associated with poorer clinical outcomes for patients. The association of NCAPH and Mcl-1 proteins with the clinical and pathological features of non-small cell lung cancer (NSCLC) remains to be elucidated. In the current study, the positive percentage of NCAPH in the non-cancerous lung tissues was revealed to be higher compared with that in NSCLC. However, the positive percentage of Mcl-1 in the non-cancerous lung tissues was lower compared with NSCLC. In addition, NCAPH high-expression patients had a higher overall survival rate compared with patients exhibiting low expression, whereas the Mcl-1 high-expression group had a lower survival rate. Pairwise association in 260 cases of NSCLC revealed that overexpression of the NCAPH protein was negatively associated with Mcl-1 expression and vice versa. The results of multivariate Cox proportional hazard regression analysis also indicated that NCAPH and Mcl-1 demonstrated potential as distinct prognostic factors that may be used in NSCLC. The expression of NCAPH and Mcl-1 may be associated with, and act as distinct molecular marks for the prediction of a poor prognosis in patients with NSCLC.

Cancer stem cells (CSCs) are a key subpopulation within tumors, characterized by their self-renewal and differentiation potential, and they drive tumor initiation, progression, metastasis, and recurrence. Recent epitranscriptomic studies have revealed that RNA modifications, including m ⁶ A, m ⁵ C, ac ⁴ C, m ⁷ G, and m ¹ A, play critical roles in maintaining CSC stemness, determining cell fate, reprogramming metabolism, and promoting therapy resistance. This review systematically summarizes the functions of different RNA modifications and their associated enzymes in CSCs. We also discuss how RNA modifications regulate core CSC signaling pathways, such as Wnt/β-catenin, Notch, Hedgehog, PI3K–AKT–mTOR, JAK/STAT, Hippo/YAP, and TGF-β/SMAD, and we highlight strategies targeting RNA modifications for CSC intervention along with their potential challenges. These findings suggest that RNA modifications and their regulators represent promising therapeutic targets in CSCs, providing a rationale for developing highly selective or combination treatment strategies.