An oncogenic role of Deleted in Liver Cancer 1 (DLC1) in metastatic melanoma

Abstract

Melanoma is a type of skin malignancy originated from neural crest-derived melanocytes. Although the mortality rate has been significantly reduced due to early cancer diagnosis and treatment, distant metastasis still exhibits much inferior survival rates compared to the early stage of this disorder. Therefore, developing new target for therapy is of particular significance in combating metastatic melanoma. DLC1 is well known for its tumor suppressor role through activating small Rho-GTPases’ (RHOA and CDC42) intrinsic capability to convert an active GTP to an inactive GDP-bound state, leading to inhibition of tumor growth and metastasis. So far, downregulation of DLC1 expression has been widely reported to associate with increased risk of various malignancies whereas elevation of its expression prevents tumor progression. In contrast to these studies, our pilot findings reveal that multiple melanoma cell lines exhibit higher levels of DLC1 than benign melanocytes and other cancer types, suggesting its unique expression profile in melanoma. Furthermore, in vitro functional assays demonstrate that silenced DLC1 inhibits proliferative, clonogenic, migratory and invasive capabilities of melanoma cells, whereas restoration of DLC1 rescued the oncogenic properties. More importantly, in lung metastasis model using nude mice, DLC1 knockdown suppresses melanoma cells colonizing to the lungs whereas their pulmonary metastases can be recovered with the reconstitution of DLC1. In addition, the manipulation of DLC1 expression does not alter the RHO-ROCK-MRLC signalling, indicating that its oncogenic effect is mediated through a RHO-independent manner. Thus, our results unravel an unprecedented paradigm-shift of DLC1 functioning as an oncogene instead of a tumor suppressor in metastatic melanoma, which may shed new light on disease pathogenesis and uncover novel therapeutic targets to treat this deadly cancer.