Background and Aims: Lenvatinib is recognized as a first-line therapy for inoperable hepatocellular carcinoma (HCC) patients. Growing evidence indicates that the lenvatinib resistance can be acquired in HCC cells via kinase rewiring. Approach and Results: We established acquired lenvatinib resistance organoids and HCC cell lines. NIMA-related coiled-coil kinase 7 (NEK7) was identified as an HCC lenvatinib acquired resistance gene by kinase CRISPR–Cas9 genetic screen. Functional analyses demonstrate that NEK7 enhanced lenvatinib resistance in HCC and NEK7 knock down or knock out display the anti-tumor effects in acquired lenvatinib HCC cells and organoids. Mechanistically, NEK7 binds to EGFR, leading to the phosphorylation of EGFR (Endothelial growth factor receptor) specifically at the serine 1070 residue, which contributes to the activation of MAPK (Mitogen-activated protein kinase) and PI3K/AKT (Phosphoinositide 3-kinase/Akt) signaling pathways. Consistently, designed inhibitory peptides targeting domain from amino acids 979 to 1099 were proved to inhibit phosphorylation of EGFR S1070 site and therapeutically inhibit anti-tumor of acquired lenvatinib resistance HCC. Conclusions: Our results unveil insights into the acquired lenvatinib resistance mechanism that NEK7 phosphorylates EGFR at S1070 to promote acquired lenvatinib resistance in HCC. Export

Post-translational modifications (PTMs) on protein lysine residues, including lactylation, methylation, acetylation, ubiquitination, and succinylation, serve as critical regulators in tumorigenesis and progression. Histone PTMs participate in tumor development by modulating chromatin structure and regulating gene expression. Notably, accumulating evidence reveals that PTMs target extensive non-histone substrates. These modifications occurring on non-histone proteins also contribute to tumor-associated biological processes. In this review, we systematically summarize the impact of non-histone PTMs on tumor and the tumor immune microenvironment (TIME). Additionally, we discuss crosstalk between distinct PTMs, which complicates the regulatory mechanisms of protein function. An in-depth research on PTMs in tumors holds new insights for exploring promising clinical therapeutic strategies.

Intrahepatic cholangiocarcinoma (iCCA), the second most common subtype of primary liver cancer around the world, is an aggressive neoplasm with high metastastic potential, which leads to a low rate of curative resections and dismal prognosis. In previous studies, Sulfatase 2 (SULF2) has been reported to regulate various important oncogenic signaling pathways and promote iCCA progression. Further research is needed to explore the role of SULF2 in iCCA metastasis. In this study, we verified the overexpression of SULF2 in iCCA tissues and its positive correlation with advanced stage and poor prognosis. Trans-well migration and invasion assay and mouse models explored the impact of SULF2 on iCCA metastasis in vitro and in vivo. We also demonstrated that SULF2 facilitated iCCA metastasis through upregulating CXCR4 transcription mediated by the transcription factor YBX1. Moreover, SULF2 could recruit USP7 to interact with YBX1 and inhibit Lys48-polyubiquitination of YBX1, stabilizing YBX1 and promoting a functional YBX1/CXCR4 axis. Combining SULF2 monoclonal antibody with SU056 had a synergistic effect in suppressing iCCA progression and metastasis of mouse models. In conclusion, SULF2 promotes iCCA progression and metastasis through an intracellular SULF2-YBX1-CXCR4 axis, and SULF2 monoclonal antibody combined with YBX1 inhibitor SU056 may be a potentially promising treatment strategy for iCCA.