Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

Abstract

Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.ubiquitination-mediated signaling | pre-clinical studies B reast cancer (BCa) is the leading invasive cancer among women worldwide. BCa-related mortality is usually caused by distant metastases rather than primary tumors (1, 2). The spread of cancer cells from primary tumors to distant organs, termed metastasis, is a multistep process in which cancer cells must (i) invade through the extracellular matrix (ECM), (ii) disseminate into the bloodstream, (iii) survive in the circulation, and (iv) extravasate and successfully colonize distant sites (3). Conventional therapeutic strategies have limited success in preventing and treating metastatic cancer, and BCa metastases can recur many years after removal of the primary tumor. This phenomenon could be due to the complex nature of metastasis itself, and, more realistically, the limitation of current treatments that are effective against primary BCa, i.e., surgical removal and localized radiotherapy, but do little to prevent metastatic recurrence. Even chemotherapy is not very effective against metastatic tumors (4). Unfortunately, the pharmaceutical industry has been reluctant to conduct metastasis prevention trials on patients with early stage cancer using survival and reduction of metastatic load as end points, because such studies are lengthy and require a large number of patients with otherwise relatively good survival prospects (4). Consequently, the development of agents that prevent metastasis from occurring and trigger regression of established metastatic lesions is an urgent unmet need.It was reported that expression of the ubiquitin conjugating enzyme (E2) Ubc13 is up-regulated in metastatic BCa (5). Ubc13, which heterodimerizes with Uev1a, catalyzes formation of lysine 63 (K63)-linked polyubiquitin chains, which control protein-protein interactions involved in DNA damage repair and protein kinase activation (6, 7). In certain immune cells, Ubc13 is required for IκB kinase (IKK)-nuclear factor κB (NF-κB) activation, but a more ubiquitous role for Ubc13 was observed in the activation of MAPK signaling (8-11). We found that Ubc13 is required for activation of mitogen-a...

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

“…41,42 Although the direct correlation between expression of cyclophilins and phosphorylation of p38MAPK has not been established, increased levels of phosphorylated p38MAPK have been described in various cancers. 8,9,[12][13][14]35,43 In this study, we found that cyclophilinmediated isomerisation could be a critical step in the activation of p38MAPK, which could explain the correlative evidence in the literature concerning the overexpression of cyclophilins and an increase in p38MAPK phosphorylation. This in turn could suggest that different cyclophilins and in particular CypA can function as a molecular switch to modulate p38MAPK signalling to adjust to environmental changes, thus modulating cancer cell survival.…”

The Stress Kinase p38α as a Target for Cancer Therapy

“…A recent report has implicated p38a, downstream of the ubiquitin-conjugating enzyme Ubc13 and the kinase TAK1, in the metastatic dissemination of breast cancer cells to the lung in mouse models. Moreover, p38a and Ubc13 expression correlates with worse overall survival in human patients with breast cancer (21).…”

“…Thus, p38a inhibitors may suffice to impair the growth of tumors where this pathway is required for cancer cell proliferation or survival, but these inhibitors could potentially stimulate tumorigenesis in other tissues. There is also evidence for dual roles of p38a in metastasis, as downregulation of p38a signaling facilitates the metastatic spread of colon cancer cells from liver to lung (18), whereas a p38a pharmacologic inhibitor attenuates breast cancer metastasis (21). The development of new therapeutic strategies clearly requires a better understanding of the specific targets involved in the different functions of p38a and how they contribute to specific tumoral processes In addition, recent data strongly implicate p38a signaling in the resistance to chemotherapeutic treatments.…”

Selecting key genes associated with osteosarcoma based on a differential expression network

“…Crucially, MEKK1 and TAK1 are also required for the metastasis of cancer cells (Cuevas et al, 2006;Safina et al, 2008). A recently published paper showed that UBC13 controls breast cancer metastasis via TAK1-p38 MAP kinase cascades (Wu et al, 2014).…”