Macropinocytosis supports the metabolic requirement of RAS‐transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS‐transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin‐binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2‐deletion construct, we demonstrate that the UBA‐domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP‐bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS‐driven cancers.

中文翻译：

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泛素结合相关蛋白 2 调节胰腺癌中 KRAS 激活和巨胞饮作用

巨胞饮作用支持 RAS 转化的胰腺导管腺癌细胞 (PDAC) 的代谢需求。然而，导致巨胞饮作用的 RAS 转化（激活）调节因子尚未确定。在此，我们报道 UBAP2（泛素结合相关蛋白 2）调节胰腺癌中 KRAS 的激活和巨胞饮作用。我们证明 UBAP2 在胰腺癌细胞系和 PDAC 患者的肿瘤组织中高表达。UBAP2 的表达与包括 PDAC 在内的多种癌症的总体生存率较差相关。沉默 UBAP2 会降低激活的 KRAS 水平，并抑制巨胞饮作用和体内肿瘤生长。使用 UBAP2 缺失构建体，我们证明 UBAP2 的 UBA 结构域对于调节巨胞饮作用和维持激活的 KRAS 水平至关重要。此外，UBAP2 调节 RAS 下游信号传导并帮助维持 RAS 的 GTP 结合形式。然而，UBAP2调节KRAS激活的确切机制尚不清楚，需要进一步研究。因此，UBAP2可作为潜在的治疗靶点来抑制激活的KRAS驱动的癌症中的巨胞饮作用和肿瘤生长。