Selected Articles from This Issue

PAX8 is recognized as an essential lineage-specific transcription factor in ovarian cancer, but the mechanism by which it regulates transcription is not well studied. In their study, Sereti and colleagues analyzed the PAX8 interactome using proximity labelling and coimmunoprecipitation and found that PAX8 interacts with the SWI/SNF complex in the nucleus. Protein fragment complementation studies revealed that the PAX8 transactivation domain is key to its interaction with the SWI/SNF complex. This interaction was subsequently assessed for its ability to colocalize to chromatin and promote transcription using ChIP‐seq and ATAC‐seq in PAX8 competent and knockout cells. The authors found overlapping peaks for PAX8 and SMARCA4, indicating their interaction on chromatin, and identified a mechanism for PAX8 dependent recruitment of the SWI/SNF complex to PAX8 target genes. This interaction was also determined to be important in ovarian cancer progression, with PAX8-mediated SWI/SNF recruitment playing a key role in cancer cell proliferation. Taken together, this study highlights the tumorigenic capacity of PAX8 and delineates the PAX8/SWI/SNF axis cooperation in ovarian cancer.RNF6, a RING finger protein and E3 ubiquitin ligase, has demonstrated a propensity to promote tumor development by mediating protein ubiquitination in multiple malignancies. To elucidate the role and mechanism of RNF6 in lung cancer, Sun and colleagues analyzed the interactome of RNF6 and conducted several knockdown studies in vitro and in vivo. Unlike reports from other cancers, they found that RNF6 is lowly expressed in lung cancer and is associated with better prognoses. Additional investigation with MTT assays and EdU staining showed that overexpression of RNF6 is associated with decreased tumorigenecity and sensitivity to cisplatin, indicating an anti-cancer function in lung cancer. RINGAP-MS/MS and IP/IB assays on lung cancer cells identified CCND2 as an RNF6-interacting protein, and the authors confirmed this interaction using a GST pulldown assay and observed their interaction in the nucleus through immunofluorescence staining. RNF6 knockdown models also revealed a T280-dependent K48-linked polyubiquitination mechanism for CCND2. Cell-cycle analysis further exhibited that RNF6 had an inhibitory effect on the CCND2/pRb signaling pathway. Overall, this study illustrates the tumor suppressive function of RNF6 in lung cancer and presents RNF6 as a novel therapeutic target for combination therapy.EGFR inhibition is a common strategy for lung cancer, while in breast cancer, inhibitors targeting both EGFR and HER2 are often used. However, EGFR inhibitors have demonstrated limited success in patients due to intrinsic and acquired resistance mechanisms. In their study, Cuellar‐Vite and colleagues aimed to overcome this resistance by identifying protein targets that can disrupt downstream EGFR signaling, such as SRC family kinases, to improve the efficacy of EGFR inhibitors. Using a reverse phase protein array and YES1 knockdown studies, the authors evaluated the utility of YES1, a non‐receptor tyrosine kinase from the SRC family that has previously been associated with EGFR inhibitor resistance. These analyses revealed a potential interaction between the YES1 and EGFR proteins and demonstrated that the EGFR gene is regulated by YES1. Using ENCODE, c‐Jun was identified as an additional mediator of EGFR expression. Cellular knockdown models and rescue experiments for c‐Jun and YES1 validated a YES1‐mediated mechanism of EGFR expression through JNK and c‐Jun modulation. Exploration of the potential impact that targeting this pathway may have on tumor growth showed enhanced anti-tumorigenic effects for combinatorial inhibition of YES1 and EGFR both in vitro and in xenografts. Altogether, this study highlights the role of YES1 in EGFR expression and demonstrates the potential clinical utility of targeting YES1 in combination with EGFR.