ALKBH5‐Mediated m⁶A Modification of XBP1 Facilitates NSCLC Progression Through the IL‐6–JAK–STAT3 Pathway

Oct 10, 2024Molecular carcinogenesis

ALKBH5 helps lung cancer grow by changing XBP1 and activating the IL-6-JAK-STAT3 signaling pathway

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Abstract

XBP1 expression is regulated by N6-methyladenosine (mA) modification, affecting NSCLC cell behavior.

ALKBH5 is identified as a regulator of mA modification and XBP1 expression in NSCLC cells.
Knockdown of ALKBH5 leads to increased mA modification and stability of XBP1 mRNA.
Overexpression of ALKBH5 decreases XBP1 mRNA stability.
IGF2BP3 enhances XBP1 mRNA stability as a reader of its mA methylation.
Knockdown of IGF2BP3 reverses the stabilization effects on XBP1 caused by ALKBH5 depletion.
ALKBH5 and IGF2BP3 together promote NSCLC cell proliferation, migration, and invasion via upregulation of XBP1.

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The X-box-binding protein 1 (XBP1) is an important transcription factor during endoplasmic reticulum stress response, which was reported as an oncogene in non-small cell lung cancer (NSCLC) tumorigenesis and development. However, the regulatory mechanism of XBP1 expression in NSCLC progression was less reported. N6-methyladenosine (mA) RNA modification is an emerging epigenetic regulatory mechanism for gene expression. This study aimed to investigate the regulatory role of the mA modification in XBP1 expression in NSCLC. We identified XBP1 as a downstream target of ALKBH5-mediated mA modification in A549 and PC9 cells. Knockdown of ALKBH5 increased the mA modification and the stability of XBP1 mRNA, while overexpression of ALKBH5 had the opposite effect. Furthermore, IGF2BP3 was confirmed to be a reader of XBP1 mA methylation and to enhance the stability of XBP1 mRNA. Additionally, IGF2BP3 knockdown significantly reversed the increase in XBP1 stability mediated by ALKBH5 depletion. In vivo and in vitro experiments demonstrated that ALKBH5/IGF2BP3 promotes the proliferation, migration, and invasion of NSCLC cells by upregulating XBP1 expression. In addition, we also showed that XBP1 promoted NSCLC cell proliferation, migration, and invasion by activating IL-6-JAK-STAT3 signaling. Our research suggested that ALKBH5-mediated mA modification of XBP1 facilitates NSCLC progression through the IL-6-JAK-STAT3 pathway. 6 6 6 6 6 6

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ALKBH5‐Mediated m⁶A Modification of XBP1 Facilitates NSCLC Progression Through the IL‐6–JAK–STAT3 Pathway

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