Abstract:
:A Rho GTPase-activating protein (RhoGAP), deleted in liver cancer 1 (DLC1), is known to function as a tumor suppressor in various cancer types; however, whether DLC1 is a tumor-suppressor gene or an oncogene in melanoma remains to be clarified. Here we revealed that high DLC1 expression was detected in most of the melanoma tissues where it was localized in both the nuclei and the cytoplasm. Functional studies unveiled that DLC1 was both required and sufficient for melanoma growth and metastasis. These tumorigenic events were mediated by nuclear-localized DLC1 in a RhoGAP-independent manner. Mechanistically, mass spectrometry analysis identified a DLC1-associated protein, FOXK1 transcription factor, which mediated oncogenic events in melanoma by translocating and retaining DLC1 into the nucleus. RNA-sequencing profiling studies further revealed MMP9 as a direct target of FOXK1 through DLC1-regulated promoter occupancy for cooperative activation of MMP9 expression to promote melanoma invasion and metastasis. Concerted action of DLC1-FOXK1 in MMP9 gene regulation was further supported by their highly correlated expression in melanoma patients' samples and cell lines. Together, our results not only unravel a mechanism by which nuclear DLC1 functions as an oncogene in melanoma but also suggest an unexpected role of RhoGAP protein in transcriptional regulation.
journal_name
Oncogenejournal_title
Oncogeneauthors
Yang X,Hu F,Liu JA,Yu S,Cheung MPL,Liu X,Ng IO,Guan XY,Wong KKW,Sharma R,Lung HL,Jiao Y,Lee LTO,Cheung Mdoi
10.1038/s41388-020-1274-8subject
Has Abstractpub_date
2020-05-01 00:00:00pages
4061-4076issue
20eissn
0950-9232issn
1476-5594pii
10.1038/s41388-020-1274-8journal_volume
39pub_type
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