Nuclear DLC1 exerts oncogenic function through association with FOXK1 for cooperative activation of MMP9 expression in melanoma

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.

A regularized functional regression model enabling transcriptome-wide dosage-dependent association study of cancer drug response

“…On the other hand, the DLC1 gene has an overall decreasing and negative effect on cancer cell survival (Spearman correlation = -0.928) which suggested that as the dosage increases, higher baseline expression of this gene can indicate higher drug sensitivity at higher dosage. Elevated expression of DLC1 has been observed in melanoma and is a well known tumour suppressor that could be a novel marker of BRAF inhibition [ 31 ]. Finally, in cases where the overall effect varies (changes between positive and negative), the effect of gene expression on the drug response depends on the drug dosage.…”

Rho GTPase signaling in cancer progression and dissemination

“…Increased nuclear DLC-1, observed in melanomas, cooperated with transcription factor FOXK1 to transactivate matrix metalloproteinase 9 (MMP-9). These effects were independent of DLC-1 RHOGAP activity (126). Nuclear DLC-1 was less efficient in disintegrating RHOA-mediated actin stress fibres (125), but whether DLC-1 oncogenic effects involve Rho GTPases is unclear.…”

A regularized functional regression model enabling transcriptome-wide dosage-dependent association study of cancer drug response

“…The 230 genes were ranked based on the estimated AUC value (Table S4), and the top 30 genes were highlighted for further analysis ( has been observed in melanoma and is a well known tumour suppressor that could be a novel marker of BRAF inhibition [31]. Finally, in cases where the overall effect varies (changes between positive and negative), the effect of gene expression on the drug response depends on the drug dosage.…”

“…On the other hand, the DLC1 gene has a decreasing (Spearman’s correlation=-0.928) and negative effect on cancer cell survival which suggested that as the dosage increases, higher baseline expression of this gene can indicate higher drug sensitivity at higher dosage. Elevated expression of DLC1 has been observed in melanoma and is a well known tumour suppressor that could be a novel marker of BRAF inhibition [31]. Finally, in cases where the overall effect varies (changes between positive and negative), the effect of gene expression on the drug response depends on the drug dosage.…”