Abstract:Background
N6-methyladenosine is the most abundant eukaryotic mRNA modification and alters a wide range of cellular processes in cancer. Therefore, defining the molecular details are critical for understanding the regulatory mechanism of m6A modification.
Results
We found that METTL3, a core m6A methyltransferase component, is upregulated and functions as an oncogene in cervical cancer. Mechanistically, METTL3 induces the degradation of m6A-modifie… Show more
“…Nuclear receptor subfamily 4A1 (NR4A1) plays diverse roles in different tumors. NR4A1 overexpression may attenuate malignant progression in some tumors and may also serve as a drug target for cancer chemotherapy [ 40 , 41 ]. Fig.…”
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.
“…Nuclear receptor subfamily 4A1 (NR4A1) plays diverse roles in different tumors. NR4A1 overexpression may attenuate malignant progression in some tumors and may also serve as a drug target for cancer chemotherapy [ 40 , 41 ]. Fig.…”
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.
“…RNA extraction, quantitative PCR, and Western blot analysis were performed as previously described. 74 The Supporting Data contains a detailed procedure and a relative primer sequence.…”
Section: Transmission Electron Microscopymentioning
Sonodynamic therapy (SDT) has considerable potential
in cancer
treatment and exhibits high tissue penetration with minimal damage
to healthy tissues. The efficiency of SDT is constrained by the complex
immunological environment and tumor treatment resistance. Herein,
a specific acoustic-actuated tumor-targeted nanomachine is proposed
to generate mechanical damage to lysosomes for cancer SDT. The hybrid
nanomachine was assembled with gold nanoparticles (GNPs) as the core
and encapsulated with macrophage exosomes modified by AS1411 aptamers
(GNP@EXO-APs) to optimize the pharmacokinetics and tumor aggregation.
GNP@EXO-APs could be specifically transferred to the lysosomes of
tumor cells. After induction with ultrasound, GNP@EXO-APs generated
strong mechanical stress to produce lysosomal-dependent cell death
in cancer cells. Notably, tumor-associated macrophages were reprogrammed
in the ultrasound environment to an antitumor phenotype. Enhanced
mechanical destruction via GNP@EXO-APs and immunotherapy of cancer
cells were verified both in vitro and in vivo under SDT. This study
provides a new direction for inside-out killing effects on tumor cells
for cancer treatment.
“…In cervical cancer, METTL3 induces m 6 A modified NR4A1 RNA degradation through the YTHDF2-DDX6 pathway to manipulate tumor metastasis. In detail, the role of NR4A1 in recruiting the LSD1/HDAC1/CoREST complex to the AKT1 promoter is weakened, and the transcriptional activity of AKT1 is promoted [ 93 ]. In papillary thyroid cancer, METTL3 stabilizes STEAP2 RNA and positively regulates STEAP2 expression in an m 6 A-dependent manner, which inhibits the Hedgehog signaling pathway and suppresses cancer metastasis [ 94 ].…”
Section: Role Of Mettl3 In Tumor Cell Migration and Invasionmentioning
As one of the most abundant epigenetic modifications in RNA, N6-methyladenosine (m6A) affects RNA transcription, splicing, stability, and posttranscriptional translation. Methyltransferase-like 3 (METTL3), a key component of the m6A methyltransferase complex, dynamically regulates target genes expression through m6A modification. METTL3 has been found to play a critical role in tumorigenesis, tumor growth, metastasis, metabolic reprogramming, immune cell infiltration, and tumor drug resistance. As a result, the development of targeted drugs against METTL3 is becoming increasingly popular. This review systematically summarizes the factors that regulate METTL3 expression and explores the specific mechanisms by which METTL3 affects multiple tumor biological behaviors. We aim to provide fundamental support for tumor diagnosis and treatment, at the same time, to offer new ideas for the development of tumor-targeting drugs.
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