Shah Parag P, Beverly Levi J
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Cancers (Basel). 2023 Jun 28;15(13):3389. doi: 10.3390/cancers15133389.
The ubiquilin family (UBQLN) of proteins consists of five closely related members (UBQLN1, UBQLN2, UBQLN3, UBQLN4, and UBQLNL) that have a high degree of similarity at the level of both amino acid and domain structure. The role of UBQLN1 and UBQLN2 in regulating processes involved in cancer progression and tumorigenesis is still not completely understood. MYC is an oncogene and is well known to play important roles in cancer progression and metastasis. Herein, we show that the loss of UBQLN1 and UBQLN2 causes increased cell viability, cell proliferation, cell migration, clonogenic potential, and cell cycle progression, which is associated with increased MYC expression. UBQLN1 and UBQLN2 interact with phosphorylated MYC and facilitate its degradation. The overexpression of UBQLN1 reverses the increased expression of MYC following the loss of UBQLN2. Further, we present evidence that decreasing MYC levels back to baseline can reverse phenotypes driven by the loss of UBQLN1 or UBQLN2. Finally, we show that loss of UBQLN1 drives tumorigenesis and lung metastasis in mice which are associated with an increase in the expression of MYC, proteins involved in cell cycle progression, and EMT. Taken together, our results suggest for the first time a novel role of UBQLN1 and UBQLN2 in regulating MYC in lung adenocarcinoma cells.
泛素连接酶家族（UBQLN）由五个密切相关的成员（UBQLN1、UBQLN2、UBQLN3、UBQLN4和UBQLNL）组成，它们在氨基酸和结构域水平上具有高度相似性。UBQLN1和UBQLN2在调节癌症进展和肿瘤发生相关过程中的作用仍未完全明确。MYC是一种癌基因，在癌症进展和转移中发挥重要作用。在此，我们表明，UBQLN1和UBQLN2的缺失会导致细胞活力、细胞增殖、细胞迁移、克隆形成潜力和细胞周期进程增加，这与MYC表达增加有关。UBQLN1和UBQLN2与磷酸化的MYC相互作用并促进其降解。UBQLN1的过表达可逆转UBQLN2缺失后MYC表达的增加。此外，我们提供的证据表明，将MYC水平降至基线可以逆转由UBQLN1或UBQLN2缺失驱动的表型。最后，我们表明，UBQLN1的缺失会驱动小鼠肿瘤发生和肺转移，这与MYC、参与细胞周期进程的蛋白质和上皮-间质转化（EMT）的表达增加有关。综上所述，我们的结果首次表明UBQLN1和UBQLN2在调节肺腺癌细胞中的MYC方面具有新作用。
