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

• Published in: Oncogene 2020-05, Vol.39 (20), p.4061-4076
• Main Authors: Yang, Xintao, Hu, Feng, Liu, Jessica Aijia, Yu, Shan, Cheung, May Pui Lai, Liu, Xuelai, Ng, Irene Oi-Lin, Guan, Xin-Yuan, Wong, Kelvin K. W., Sharma, Rakesh, Lung, Hong Lok, Jiao, Yufei, Lee, Leo Tsz On, Cheung, Martin
• Format: Article
• Language: English
• Subjects: 101/58; 13/106; 13/109; 14/33; 38/39; 42/35; 42/41; 631/67/1813/1634; 631/67/395; 64/60; Apoptosis; Cell Biology; Cell Line, Tumor; Cytoplasm; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gelatinase B; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene regulation; GTPase-activating protein; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanosine triphosphatases; Human Genetics; Humans; Internal Medicine; Liver; Liver cancer; Mass spectroscopy; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Medicine; Medicine & Public Health; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metastases; Metastasis; Nuclei; Oncology; Proteins; Ribonucleic acid; RNA; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1274-8

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.