Persistent infection with high-risk human papillomaviruses (HPVs), notably HPV-16 and HPV-18, underlies most cervical cancers and many head and neck cancers. Here, we report the structural and functional basis by which the viral oncoprotein E7 hijacks host CRL2ZER1 to degrade retinoblastoma (Rb) protein and drive E2F-dependent proliferation. Crystal structures reveal that the N-terminal MH/N-degron of E7 engages a defined pocket within the armadillo (ARM)-repeat domain of ZER1. Disruption of this interface abolishes E7-ZER1 binding, prevents Rb degradation, silences E2F transcriptional programs, and impairs proliferation of HPV-positive cancer cells. Guided by these insights, we identify a first-in-class small-molecule inhibitor that blocks E7-ZER1 association, restores Rb stability, and selectively suppresses HPV-positive tumor growth in vivo. These results define a viral mimicry mechanism and nominate the ZER1 degron pocket as a ligandable therapeutic target for HPV-driven malignancies, highlighting translational opportunities for targeted therapy.
Colorectal cancer liver metastasis (CRLM) is the primary cause of CRC-related mortality, with inevitable chemoresistance to targeted therapies and immunotherapy. N6-methyladenosine (m6A), as a crucial epigenetic regulator of gene expression and cellular physiology, involved in the pathogenesis of CRLM. Precise manipulation of m6A modifications could offer a non-pharmacological precision treatment for many diseases. However, the precise editing of m6A modification in regulating CRLM progression remains elusive. Here we integrated multi-omics and identified zinc finger and BTB domain-containing 7A (ZBTB7A) as an m6A-modified transcription factor that promoted CRLM. Mechanistically, METTL3-mediated m6A modification of ZBTB7A facilitated recognition by the m6A reader YTHDF1/3 complex, enhancing its translation and expression. This m6A-dependent regulation promoted CRLM progression via activation of the ARHGAP26/Rho GTPase signaling axis. Notably, we applied a targeted RNA m6A erasure (TRME) system to achieve site-specific demethylation at a single site (m6A_site_411666) within ZBTB7A mRNA, without perturbing m6A abundance. Temporal demethylation at this site is sufficient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m6A-mediated CRLM and positions m6A precise editing as a promising therapy in the preclinical treatment of CRLM.
Xue-Na Chen, Shu-Qiang Zhao, Bochen Liu et al.· Molecular Cancer· 0 citations
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