Pellino-1 (PELI1) is an E3 ubiquitin ligase acting as a key regulator for the inflammation and autoimmunity via the ubiquitination of the substrate proteins. There is increasing evidence to support that PELI1 functions as an oncoprotein in tumorigenesis and metastasis. However, the molecular mechanism underlying the high expression and oncogenic roles of PELI1 in cancers remains limited. Herein, we revealed a novel regulation mechanism by which PELI1 and EGFR cooperate to promote breast cancer metastasis. EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. The co-inhibition of the PELI1-EGFR showed synergetic effect to repress breast cancer metastasis. Furthermore, we identified a compound S62 as a small molecule disruptor of PELI1/EGFR that effectively repressed breast cancer metastasis. Our study not only uncovered the emerging roles of PELI1/EGFR interaction in the progression of breast cancer, but also provided an effective strategy for the inhibition of metastasis in breast cancer.

Pellino-1 (PELI1) 是一种 E3 泛素连接酶，通过底物蛋白的泛素化充当炎症和自身免疫的关键调节剂。越来越多的证据支持 PELI1 在肿瘤发生和转移中起癌蛋白的作用。然而，PELI1 在癌症中高表达和致癌作用的分子机制仍然有限。在此，我们揭示了 PELI1 和 EGFR 协同促进乳腺癌转移的新调控机制。EGFR 与乳腺癌中的 PELI1 表达呈正相关，其激活导致 PELI1 在 Tyr154 和 Thr264 位点磷酸化，随后激活其 E3 泛素连接酶。同时，PELI1 通过 K63 连接的多聚泛素化与 EGFR 物理相互作用并增强其稳定性。PELI1-EGFR 的共同抑制显示出抑制乳腺癌转移的协同作用。此外，我们将化合物 S62 鉴定为 PELI1/EGFR 的小分子破坏剂，可有效抑制乳腺癌转移。我们的研究不仅揭示了 PELI1/EGFR 相互作用在乳腺癌进展中的新作用，而且为抑制乳腺癌转移提供了有效策略。