Biological and pharmacological roles of m6A modifications in cancer drug resistance

Zaoqu Liu1,2,3, Haijiao Zou4, Qin Dang5

  • 1Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.

Molecular Cancer
|December 14, 2022
PubMed

Insights

Cancer drug resistance is a major challenge. N6-methyladenosine (m6A) RNA modification plays a key role in therapy resistance by affecting cancer cell processes and the tumor microenvironment, offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Oncology

Background:

  • Cancer drug resistance is a significant clinical challenge, hindering effective treatment outcomes.
  • N6-methyladenosine (m6A) is the most prevalent reversible epigenetic RNA modification, crucial in gene regulation.
  • Dysregulation of m6A regulators (writers, erasers, readers) is implicated in various cancers, promoting tumorigenesis and metastasis.

Purpose of the Study:

  • To review the multifaceted role of m6A RNA modification in the development of cancer therapy resistance.
  • To elucidate how m6A alterations impact drug efficacy through various molecular and cellular mechanisms.
  • To highlight the therapeutic potential of targeting m6A regulators for overcoming drug resistance.

Main Methods:

  • Literature review of studies investigating m6A modification in cancer drug resistance.
  • Analysis of molecular mechanisms by which m6A affects drug response, including transporter regulation, DNA repair, and signaling pathways.
  • Examination of the role of m6A in cancer stemness, immune microenvironment, and exosomal communication.

Main Results:

  • m6A alterations influence drug efficacy by modulating multidrug efflux transporters, drug-metabolizing enzymes, and drug targets.
  • m6A dysregulation contributes to resistance by affecting DNA damage repair, apoptosis, autophagy, and bypass signaling.
  • Changes in m6A are linked to enhanced cancer stemness, altered tumor immune microenvironment, and modified exosomal non-coding RNA profiles.

Conclusions:

  • m6A RNA modification is a critical determinant of cancer drug resistance through diverse mechanisms.
  • Targeting m6A regulators with small molecules shows promise for overcoming therapeutic resistance in various cancers.
  • Inhibitors and activators of m6A-modified proteins represent a potential avenue for developing novel anticancer therapies to combat resistance.

Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.4K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
Phase II Reactions: Methylation Reactions01:17

Phase II Reactions: Methylation Reactions

Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
281
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.1K