A new ubiquitin-conjugating enzyme found to be critical in the breast cancer metastasis

Researchers from University of California, San Diego have identified an enzyme that controls the spread of breast cancer. This finding was reported in PNAS and offer new insights of understanding the metastasis of breast cancer.

Breast cancer is the leading invasive cancer among women worldwide. Its metastatic recurrence can happen many years after the removal of the primary tumor and cause the mortality. The current treatments, including surgical removal and localized radiotherapy, are effective against primary Breast cancer, but could do little to prevent metastatic recurrence. Even Chemotherapy is not helpful to prevent metastatic recurrence.

In this study, researchers have demonstrated an ubiquitin conjugating enzyme Ubc13, which could catalyze K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by Breast cancer cells. Ubc13 is required for TGF?-induced non-SMAD signaling via TAK1 and p38, a pathway that is first activated in the primary tumor. The study has identified an Ucb13- and p38-dependent metastatic gene signature, explaining how p38 may control metastasis and providing a measure for monitoring the effectiveness of pharmacologic p38 inhibition, which inhibits the growth of established metastatic lesions. It suggests that p38 inhibition should be considered as a potential treatment for metastatic breast cancer.

Researchers from University of North Carolina have recently identified a critical splicing factor RBM4 whose expression decreases dramatically in many human cancers, including lung cancer and breast cancer, etc. This result may provide ideas that would enable therapeutic targeting of deregulated splicing and open new avenues for cancer therapy. This study was published on Cancer Cell.

Alternative Spicing(AS) plays a vital role in the intricate regulation of protein function and aberrant splicing is closely associated with human cancers. However, the mechanistic details underlying these connections are largely unknown. Investigating splicing factors that play vital roles in cancer progression is a promising way to find the therapeutic anti-cancer target.

In this research, scientists report a splicing factor RBM4 suppresses proliferation and migration of various cancer cells by specifically controlling cancer-related splicing. RBM4 could regulate Bcl-x splicing to induce apoptosis, and coexpression of Bcl-xL partially reverses the RBM4-mediated tumor suppression. Further, RBM4 antagonizes an oncogenic splicing factor, SRSF1, to inhibit mTOR activation. Among many cancer patients, RBM4 expression stays in a very low level and its level correlates positively with improved survival.

This study represents a detailed mechanism of cancer-related splicing dysregulation and establishes RBM4 as a tumor suppressor with therapeutic potential.

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