METTL3-m6A-EGFR-axis drives lenvatinib resistance in hepatocellular carcinoma

Wang, Lina; Yang, Qingxia; Zhou, Qiongjie; Fang, F.; Lei, Kai; Liu, Ziqin; Zheng, Gaomin; Zhu, Lefan; Huo, Jihui; Li, Xiaoxing; Peng, Sui; Lin, Shuibin; Huang, Manling; Xu, Lixia

doi:10.1016/j.canlet.2023.216122

Cited by 47 publications

(27 citation statements)

References 21 publications

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“…Our study revealed that the knockdown of METTL3 inhibited cell proliferation and expedited the rate of apoptosis in goat granulosa cells. These findings are consistent with previous reports where the activation of METTL3 was found to enhance the self‐renewal and proliferation of intrahepatic cholangiocarcinoma cells, 28 and its inhibition led to an increase in cell apoptosis upon lenvatinib treatment in MHCC97H and Huh7‐LR cell lines 29 . The secretion of growth hormone and testosterone were modulated by m6A modification according to recent studies 30,31 .…”

Section: Discussionsupporting

confidence: 92%

“…There are plenty researches reporting that m6A participating in cell proliferation and apoptosis 28,29 . Our study revealed that the knockdown of METTL3 inhibited cell proliferation and expedited the rate of apoptosis in goat granulosa cells.…”

Section: Discussionmentioning

confidence: 56%

“…There are plenty researches reporting that m6A participating in cell proliferation and apoptosis. 28,29 Our study revealed that the knockdown of METTL3 inhibited cell proliferation and expedited the rate of apoptosis in goat granulosa cells. These findings are consistent with previous reports where the activation of METTL3 was found to enhance the self-renewal and proliferation of intrahepatic cholangiocarcinoma cells, 28 and its inhibition led to an increase in cell apoptosis upon lenvatinib treatment in MHCC97H and Huh7-LR cell lines.…”

Section: Discussionmentioning

confidence: 79%

“…These findings are consistent with previous reports where the activation of METTL3 was found to enhance the self-renewal and proliferation of intrahepatic cholangiocarcinoma cells, 28 and its inhibition led to an increase in cell apoptosis upon lenvatinib treatment in MHCC97H and Huh7-LR cell lines. 29 The secretion of growth hormone and testosterone were modulated by m6A modification according to recent studies. 30,31 While in this study, we found that the reduction in goat granulosa cell number was responsible for the decrease in hormone concentrations.…”

Section: Discussionmentioning

confidence: 99%

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N6‐methyladenosine methyltransferase METTL3 modulates the cell cycle of granulosa cells via CCND1 and AURKB in Haimen goats

Liu,

Zhou,

et al. 2023

The FASEB Journal

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N6‐methyladenosine (m6A) plays a crucial role in many bioprocesses across species, but its function in granulosa cells during oocyte maturation is not well understood in animals, especially domestic animals. We observed an increase in m6A methyltransferase‐like 3 (METTL3) in granulosa cells during oocyte maturation in Haimen goats. Our results showed that knockdown of METTL3 disrupted the cell cycle in goat granulosa cells, leading to aggravated cell apoptosis and inhibition of cell proliferation and hormone secretion. Mechanistically, METTL3 may regulate the cell cycle in goat granulosa cells by mediating Aurora kinase B (AURKB) mRNA degradation in an m6A‐YTH N6‐methyladenosine RNA binding protein 2 (YTHDF2) manner and participating in AURKB transcription via the Cyclin D1 (CCND1)‐Retinoblastoma protein (RB)‐E2F transcription factor 1 (E2F1) pathway. Overall, our study highlights the essential role of METTL3 in granulosa cells during oocyte maturation in Haimen goats. These findings provide a theoretical basis and technical means for understanding how RNA methylation participates in oocyte maturation through granulosa cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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N6‐methyladenosine methyltransferase METTL3 modulates the cell cycle of granulosa cells via CCND1 and AURKB in Haimen goats

Liu,

Zhou,

et al. 2023

The FASEB Journal

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“…Increasing evidence has emphasized the role of m6A in chemotherapy resistance 20,40 . For instance, the METTL3‐EGFR axis enhances resistance to lenvatinib in hepatocellular carcinoma 41 . In ovarian cancer, Nicotinamide N‐methyltransferase (NNMT) mRNA is demethylated and upregulated by Fat mass and obesity‐associated protein (FTO), thereby increasing sensitivity to platinum 42 .…”

Section: Discussionmentioning

confidence: 99%

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A‐dependent DAPK3 degradation

Bai,

Chen,

Zhang

et al. 2023

Cancer Science

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N6‐methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA‐binding protein YT521‐B homology domain‐containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP‐seq), m6A‐modified RIP‐seq, and RNA sequencing, which revealed that death‐associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3′‐UTR of DAPK3 mRNA and facilitates its degradation in an m6A‐dependent manner. DAPK3 inhibition restores the tumor‐suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A‐dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.

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Recent Advances in RNA‐Targeted Cancer Therapy

Li,

Zhu,

et al. 2023

ChemBioChem

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Ribonucleic acid (RNA) plays a pivotal role in gene regulation and protein biosynthesis. Interfering the physiological function of key RNAs to induce cell apoptosis holds great promise for cancer treatment. Many RNA‐targeted anti‐cancer strategies have emerged continuously. Among them, RNA interference (RNAi) has been recognized as a promising therapeutic modality for various disease treatments. Nevertheless, the primary obstacle in siRNA delivery‐escaping the endosome and crossing the plasma membrane severely impedes its therapeutic potential. Thus far, a variety of nanosystems as well as carrier‐free bioconjugation for siRNA delivery have been developed and employed to enhance the drug delivery and anti‐tumor efficiency. Besides, the use of small molecules to target specific RNA structures and disrupt their function, along with the covalent modification of RNA, have also drawn tremendous attention recently owing to high therapeutic efficacy. In this review, we will provide an overview of recent progress in RNA‐targeted cancer therapy including various siRNA delivery strategies, RNA‐targeting small molecules, and newly emerged covalent RNA modification. Finally, challenges and future perspectives faced in this research field will be discussed (Figure 1).

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METTL3-m6A-EGFR-axis drives lenvatinib resistance in hepatocellular carcinoma

Cited by 47 publications

References 21 publications

N6‐methyladenosine methyltransferase METTL3 modulates the cell cycle of granulosa cells via CCND1 and AURKB in Haimen goats

N6‐methyladenosine methyltransferase METTL3 modulates the cell cycle of granulosa cells via CCND1 and AURKB in Haimen goats

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A‐dependent DAPK3 degradation

Recent Advances in RNA‐Targeted Cancer Therapy

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