N⁶‐Methyladenosine‐Modified CBX1 Regulates Nasopharyngeal Carcinoma Progression Through Heterochromatin Formation and STAT1 Activation

Abstract

Epitranscriptomic remodeling such as N⁶ -methyladenosine (m⁶ A) modification plays a critical role in tumor development. However, little is known about the underlying mechanisms connecting m⁶ A modification and nasopharyngeal carcinoma (NPC) progression. Here, CBX1 is identified, a histone methylation regulator, to be significantly upregulated with m⁶ A hypomethylation in metastatic NPC tissues. The m⁶ A-modified CBX1 mRNA transcript is recognized and destabilized by the m⁶ A reader YTHDF3. Furthermore, it is revealed that CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation. In addition to its oncogenic effect, CBX1 can facilitate immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. Clinically, CBX1 serves as an independent predictor for unfavorable prognosis in NPC patients. The results reveal a crosstalk between epitranscriptomic and epigenetic regulation in NPC progression, and shed light on the functions of CBX1 in tumorigenesis and immunomodulation, which may provide an appealing therapeutic target in NPC.