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Review
. 2024 Jan-Dec:31:10732748241256819.
doi: 10.1177/10732748241256819.

Research Advances in the Roles of N6-Methyladenosine Modification in Ovarian Cancer

Yuhong Zhang  1   2   3 , Yufeng Ling  4 , Ying Zhou  1   2   3 , Xiu Shi  1 , Fangrong Shen  1 , Jinhua Zhou  1 , Youguo Chen  1 , Fan Yang  5   6 , Yanzheng Gu  3 , Juan Wang  1
Affiliations
Review

Research Advances in the Roles of N6-Methyladenosine Modification in Ovarian Cancer

Yuhong Zhang et al. Cancer Control. 2024 Jan-Dec.

Abstract

Ovarian cancer (OC) is the most lethal gynecological tumor, characterized by its insidious and frequently recurring metastatic progression. Owing to limited early screening methods, over 70% of OC cases are diagnosed at advanced stages, typically stage III or IV. Recently, N6-methyladenosine (m6A) modification has emerged as a hotspot of epigenetic research, representing a significant endogenous RNA modification in higher eukaryotes. Numerous studies have reported that m6A-related regulatory factors play pivotal roles in tumor development through diverse mechanisms. Moreover, recent studies have indicated the aberrant expression of multiple regulatory factors in OC. Therefore, this paper comprehensively reviews research advancements concerning m6A in OC, aiming to elucidate the regulatory mechanism of m6A-associated regulators on pivotal aspects, such as proliferation, invasion, metastasis, and drug resistance, in OC. Furthermore, it discusses the potential of m6A-associated regulators as early diagnostic markers and therapeutic targets, thus contributing to the diagnosis and treatment of OC.

Keywords: N6-methyladenosine (m6A); diagnosis; endogenous RNA modification; epigenetic research; metastatic progression; ovarian cancer; prognosis; treatment; tumor microenvironment.

Plain language summary

Ovarian cancer (OC) presents a formidable challenge in the medical field, often detected at advanced stages, necessitating urgent exploration of diagnostic and therapeutic avenues. This review delves into the intricate role of N6-methyladenosine (m6A) RNA modification in OC, a dynamic epigenetic process increasingly recognized for its regulatory role in cancer biology. Highlighting recent advancements, the review sheds light on how m6A-related factors influence crucial aspects of OC progression, including tumor growth, metastasis, and resistance to treatment. Specifically, m6A methyltransferases, binding proteins, and demethylases exert multifaceted effects on OC progression, influencing the expression of pivotal oncogenes and tumor suppressors. While promising, translating these insights into effective therapies requires further investigation. By comprehensively understanding the influence of m6A on OC, there lies hope for developing improved diagnostic techniques and novel treatment strategies to combat this complex disease.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Summary diagram illustrating m6A methyltransferase regulation in ovarian cancer (OC) development. The methyltransferase complex mediates m6A modification, with METTL3, METTL14, WTAP, and VIRMA independently influence the tumorigenesis, metastasis, and drug resistance of OC. METTL3 promotes OC progression by upregulating the expression of AXL, EIF3C, CSF-1, FZD-10, AKT, BIRC5, VGLL, RIPK4, pri-miR-1264, pri-miR-126-5p, lncRHPN1-AS1, and circPLPP4, while inhibiting the expression of IFFO1 and lncMEG3. WTAP stimulates the malignant biological behavior of OC by upregulating the expression of AKT, ERK, JNK, p38, FAM76A, HBS1L, and miR-200 and inhibiting EGR3 expression. METTL14 and VIRMA respectively act on TROAP and ENO1, exerting inhibitory and promoting effects on OC.
Figure 2.
Figure 2.
Summary diagram illustrating m6A-binding protein regulation in ovarian cancer (OC) development. M6A-modified RNAs interact with m6A-binding proteins, exerting various biological functions. This review primarily summarizes the research on YTHDF1, YTHDF2, IGF2BP1, IGF2BP2, and HNRNPA2B1 in OC. YTHDF1 enhances EIF3C and TRIM29 translation and stabilizes RIPK4 expression, while YTHDF2 promotes BMF expression and suppresses miR-145 and lncMEG3, facilitating OC progression. IGF2BP1 and IGF2BP2 promote SRF, BIRC5, SNAI1, VGLL1, circPLPP4, and circNFIX expression, promoting the malignant development of OC. However, that the context-dependent regulation of OC by IGF2BP1 is exemplified by its positive modulation of lncUBA6-AS1, which exerts anticancer effects. HNRNPA2B1 regulates CDK19 expression, further promoting OC progression.
Figure 3.
Figure 3.
Summary diagram illustrating m6A demethylase regulation in ovarian cancer (OC) development. FTO and ALKBH5 are key demethylases that modulate biological functions by removing m6A modifications. In OC research, FTO acts as a tumor suppressor gene, inhibiting the expression of genes, such as PDE4B, PDE1C, SNAI1, NMMT, ATG5, ATG7, FZD10, and lncRP5-991G20.1, by eliminating m6A modifications, thus suppressing OC progression. Conversely, ALKBH5 exhibits contrasting effects, promoting OC progression by upregulating the expression of HuR, Bcl-2, JAK2, ITGB1, and NANOG.
Figure 4.
Figure 4.
Summary diagram illustrating the effects of m6A-related regulatory factors on various clinical phenotypes of ovarian cancer (OC). This review categorizes and summarizes experimental studies, identifying 4 main clinical phenotypes of OC regulated by m6A modifications: proliferation, metastasis, drug resistance, and others. Most studies indicate the roles of m6A-related regulatory factors in regulating OC proliferation and metastasis. Apart from FTO and METTL14, most factors promote these processes. Several studies have elucidated the regulatory mechanisms of METTL3, IGF2BP1, YTHDF1, FTO, and ALKBH5 in OC drug resistance, with conclusions largely parallel to those regarding proliferation and metastasis. However, research on immune-related phenotypes, metabolism, autophagy, and other aspects remains limited. Only IGF2BP1 has been reported to promote immune evasion by upregulating circNFIX, while circRAB11FIP1 promotes autophagy through FTO-mediated upregulation of ATG5 and ATG7.
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