USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity

Abstract

Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. KrasG12D mice lacking Beclin 1 display retarded lung tumor growth. Knockdown of USP5 or knockout of Becn1 leads to increased senescence and reduced autophagy. Mechanistically, KRAS elevates ROS to induce USP5 homodimer formation by forming the C195 disulfide bond, resulting in stabilization and activation of USP5. Together, these results demonstrate that activation of the USP5-Beclin 1 axis is pivotal in overriding intrinsic p53-dependent senescence in Kras-driven lung cancer development.

PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity

“…Given its important role of in regulating γ c stability, USP5 can be a potential target for cancer immunotherapy. Unfortunately, USP5 is aberrantly expressed in human cancers and promotes tumor growth and metastasis, 62 – 64 which may limit its application as a target for cancer immunotherapy.…”

Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

“…Moreover, USP9X, USP10, and USP13 have been confirmed as deubiquitinases that can mediate the deubiquitination of Beclin-1, thus modulating autophagy activity 178 , 179 . Recently, Kras-mediated USP5 activation is reported to deubiquitinate K48-linked polyubiquitination of Beclin-1 and stabilize Beclin-1, resulting in autophagy and p53 protein instability, thereby promoting Kras-driven lung tumor growth 180 .…”

Deubiquitinating enzyme JOSD2 affects susceptibility of non-small cell lung carcinoma cells to anti-cancer drugs through DNA damage repair

“…尽管 USP5 和 PSMD14 在预后分析中显示与患者预后无显著相关性，本研究未纳入考察，但两者在NSCLC和其他肿瘤中的作用有广泛报道 ［ 22 - 24 ］ 。例如，USP5被证实直接结合并介导细胞核Beclin 1的去泛素化，从而稳定Beclin 1并促进p53的特异性降解，在KRAS突变驱动的肺癌中发挥关键作用 ［ 22 ］ 。此外，也有研究证实USP5直接结合并移除程序性死亡蛋白-1上的多聚泛素链，从而促进程序性死亡蛋白-1稳定和免疫疗法的耐受性 ［ 23 ］ 。除此之外，PSMD14也被证实通过调控E2F1的去泛素化激活AKT信号通路，并最终介导头颈部鳞状细胞癌的化学耐药 ［ 24 ］ 。以上报道提示，尽管本研究中所使用的筛选方法具有较高的普适性，仍须对排除在外的潜在靶点进一步研究。…”