No abstract

Ubiquitin-conjugating enzyme E2C (UBE2C) mediates the ubiquitylation chain formation via the K11 linkage. While previous in vitro studies showed that UBE2C plays a growth-promoting role in cancer cell lines, the underlying mechanism remains elusive. Still unknown is whether and how UBE2C plays a promoting role in vivo.Here we reported that UBE2C is indeed essential for growth and survival of lung cancer cells harboring Kras mutations, and UBE2C is required for Kras G12D -induced lung tumorigenesis, since Ube2c deletion significantly inhibits tumor formation and extends the life-span of mice. Mechanistically, Kras G12D induces expression of UBE2C, which couples with APC/C CDH1 E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of the mTORC signals. Importantly, DEPTOR levels are fluctuated during cell cycle progression in a manner dependent of UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescues the tumor inhibitory effect of Ube2c deletion in the Kras G12D lung tumor model, indicating a causal role of Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an oncogene-tumor suppressor cascade that regulates cell cycle progression and autophagy and validates that UBE2C is an attractive target for lung cancer associated with Kras mutations.

In the past decades, breast surgeons have changed the clinical practice in the surgical treatment of breast cancer, by performing sentinel lymph node biopsy (SLNB) instead of performing axillary lymph node dissection (ALND) in axillary lymph node clinically negative breast cancer patients. ALND can also be avoided in SLN-positive patients who meet the Z-0011 criteria. However, the postoperative complications of SLNB and ALND, such as the secondary upper extremity lymphedema, are common and need effective solutions to prevent as soon as possible. The axillary reverse mapping (ARM) technique has been developed to map and preserve arm lymphatic drainage during ALND and/or SLNB, thereby minimizing arm lymphedema. However, the success of ARM in reducing lymphedema has not been exactly determined. If ARM can be confirmed to be both effective and oncologically safe in preventing lymphedema, this technique should be recommended in the management of breast cancer treatment.

SUMMARY Anaphase-promoting complex/cyclosome (APC/C) is a well-characterized E3 ligase that couples with UBE2C and UBE2S E2s for substrate ubiquitylation by the K11 linkage. Our recent data show that SAG/RBX2/ROC2, a RING component of Cullin-RING E3 ligase, also complexes with these E2s for K11-linked substrate polyubiquitylation. Whether these two E3s cross-talk with each other was previously unknown. Here, we report that SAG competes with APC2 for UBE2C/UBE2S binding to act as a potential endogenous inhibitor of APC/C, thereby regulating the G2-to-M progression. As such, SAG knockdown triggers premature activation of APC/C, leading to mitotic slippage and resistance to anti-microtubule drugs. On the other hand, SAG itself is a substrate of APC/C CDH1 for targeted degradation at the G1 phase. The degradation-resistant mutant of SAG-R98A/L101A accelerates the G1-to-S progression. Our study reveals that the negative cross-talk between SAG and APC/C is likely a mechanism to ensure the fidelity of cell cycle progression.

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