Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer.
Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer.
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DOI：
10.1096/fj.201902826rr
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发表时间：
2020-09
期刊：
影响因子：
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通讯作者：
Mukherjee P
中科院分区：
文献类型：
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作者：
Xiong X;Rao G;Roy RV;Zhang Y;Means N;Dey A;Tsaliki M;Saha S;Bhattacharyya S;Dhar Dwivedi SK;Rao CV;McCormick DJ;Dhanasekaran D;Ding K;Gillies E;Zhang M;Yang D;Bhattacharya R;Mukherjee P
巨胞饮支持RAS转化的胰腺导管腺癌细胞（PDAC）的代谢需求。然而，调节RAS转化（激活），导致巨胞饮尚未确定。在此，我们报告UBAP2（泛素结合相关蛋白2），调节胰腺癌中KRAS和巨胞饮的激活。我们证明UBAP 2在胰腺癌细胞系和PDAC患者的肿瘤组织中都高度表达。UBAP 2的表达与包括PDAC在内的几种癌症的总体生存率相关。沉默UBAP2降低活化的KRAS水平，并抑制体内巨胞饮和肿瘤生长。使用UBAP2缺失构建体，我们证明了UBAP2的UBA结构域对于调节巨胞饮和维持激活的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处于GTP结合形式。然而，UBAP 2调节KRAS激活的确切机制尚不清楚，需要进一步研究。因此，UBAP 2可以被开发为潜在的治疗靶点，以抑制活化的KRAS驱动的癌症中的巨胞饮和肿瘤生长。
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 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 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 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.