NUPR1 maintains autolysosomal efflux by activating <i>SNAP25</i> transcription in cancer cells

In the advanced stages of cancer, autophagy is thought to promote tumor progression through its ability to mitigate various cellular stresses. However, the details of how autophagy is homeostatically regulated in such tumors are unknown. Here, we report that NUPR1 (nuclear protein 1, transcriptional regulator), a transcriptional coregulator, is aberrantly expressed in a subset of cancer cells and predicts low overall survival rates for lung cancer patients. NUPR1 regulates the late stages of autolysosome processing through the induction of the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE-associated protein VAMP8. NUPR1 depletion deregulates autophagic flux and impairs autolysosomal clearance, inducing massive cytoplasmic vacuolization and premature senescence <i>in vitro</i> and tumor suppression <i>in vivo</i>. Collectively, our data show that NUPR1 is a potent regulator of autolysosomal dynamics and is required for the progression of some epithelial cancers.

在癌症进展晚期，细胞自噬（autophagy）被认为可通过缓解多种细胞应激来促进肿瘤进展。然而，此类肿瘤中细胞自噬的稳态调控机制尚未明确。本研究发现，转录共调控因子NUPR1（核蛋白1，转录调节因子）在部分癌细胞中异常表达，且与肺癌患者较低的总生存率显著相关。NUPR1可通过诱导SNARE蛋白SNAP25调控自噬溶酶体加工的晚期阶段，SNAP25可与溶酶体SNARE相关蛋白VAMP8形成复合物。敲低NUPR1会破坏自噬流、损害自噬溶酶体清除功能，在体外（in vitro）诱导大规模细胞质空泡化与早衰，在体内（in vivo）则可抑制肿瘤生长。综上，本研究数据表明NUPR1是自噬溶酶体动态平衡的强效调控因子，且对部分上皮癌的进展不可或缺。