ALKBH5 regulates paclitaxel resistance in NSCLC via inhibiting CEMIP-mediated EMT

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• N6-methyladenosine (m6A) is a key mRNA modification linked to cancer progression.
• ALKBH5, an m6A demethylase, is frequently dysregulated in cancers, but its role in non-small cell lung cancer (NSCLC) chemo-resistance is unclear.

Purpose of the Study:

• To investigate the function and mechanism of ALKBH5 in NSCLC pathogenesis and paclitaxel (PTX) resistance.
• To elucidate the relationship between ALKBH5, epithelial-mesenchymal transition (EMT), and chemo-sensitivity in NSCLC.

Main Methods:

• Analysis of ALKBH5 expression in PTX-resistant NSCLC cells and patient prognosis.
• Over-expression and knockdown experiments to assess ALKBH5's effect on cell proliferation, chemo-sensitivity, and EMT.
• RNA-sequencing, real-time PCR, and western blotting to identify downstream targets and elucidate mechanisms.

Main Results:

• ALKBH5 expression is reduced in PTX-resistant NSCLC cells and associated with poor prognosis.
• ALKBH5 over-expression suppressed proliferation, enhanced chemo-sensitivity, and reversed EMT in PTX-resistant cells.
• ALKBH5 negatively regulates CEMIP by decreasing CEMIP mRNA stability, identifying CEMIP as a downstream target.

Conclusions:

• The ALKBH5/CEMIP axis plays a critical role in modulating EMT in NSCLC.
• ALKBH5 functions as a tumor suppressor by regulating CEMIP stability and influencing chemo-sensitivity to PTX.
• Targeting the ALKBH5/CEMIP pathway may offer therapeutic strategies for overcoming PTX resistance in NSCLC.