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1847.Full-Text.Pdf Published OnlineFirst January 29, 2016; DOI: 10.1158/0008-5472.CAN-15-1752 Cancer Molecular and Cellular Pathobiology Research RASSF1A Directly Antagonizes RhoA Activity through the Assembly of a Smurf1-Mediated Destruction Complex to Suppress Tumorigenesis Min-Goo Lee, Seong-In Jeong, Kyung-Phil Ko, Soon-Ki Park, Byung-Kyu Ryu, Ick-Young Kim, Jeong-Kook Kim, and Sung-Gil Chi Abstract RASSF1A is a tumor suppressor implicated in many tumorigenic as Rhotekin. As predicted on this basis, RASSF1A competed with processes; however, the basis for its tumor suppressor functions are Rhotekin to bind RhoA and to block its activation. RASSF1A not fully understood. Here we show that RASSF1A is a novel mutants unable to bind RhoA or Smurf1 failed to suppress antagonist of protumorigenic RhoA activity. Direct interaction RhoA-induced tumor cell proliferation, drug resistance, epitheli- between the C-terminal amino acids (256–277) of RASSF1A and al–mesenchymal transition, migration, invasion, and metastasis. active GTP-RhoA was critical for this antagonism. In addition, Clinically, expression levels of RASSF1A and RhoA were inversely interaction between the N-terminal amino acids (69-82) of correlated in many types of primary and metastatic tumors and RASSF1A and the ubiquitin E3 ligase Smad ubiquitination regu- tumor cell lines. Collectively, our findings showed how RASSF1A latory factor 1 (Smurf1) disrupted GTPase activity by facilitating may suppress tumorigenesis by intrinsically inhibiting the tumor- Smurf1-mediated ubiquitination of GTP-RhoA. We noted that the promoting activity of RhoA, thereby illuminating the potential RhoA-binding domain of RASSF1A displayed high sequence mechanistic consequences of RASSF1A inactivation in many can- homology with Rho-binding motifs in other RhoA effectors, such cers. Cancer Res; 76(7); 1847–59. Ó2016 AACR. Introduction RASSF1A is one of the most heavily methylated genes in human cancers and restoration of its expression decreases in The Ras-association domain family (RASSF) of proteins vitro colony formation, suppresses anchorage-independent comprises 10 members encoded by different genes growth, and reduces in vivo tumorigenicity (6, 7). RASSF1A (RASSF1–RASSF10), which share the presence of the RA interacts with proapoptotic MST1 and MST2, known to activate domain (1). The RASSF1 gene located at 3p21.3 is the best the c-Jun N-terminal kinase pathway and also enhances death characterized RASSF member that is epigenetically silenc- receptor–evoked apoptosis by binding to modulator of apo- ed in a wide variety of adult and childhood cancers (2–4). ptosis 1 (MOAP1), a Bax-binding protein and stimulating a The RASSF1 gene generates seven tissue-specifictranscripts complex formation with TNFa receptor-1 (4, 8–10). RASSF1A (RASSF1A-G) and two major variants, RASSF1A and C,are inhibits cyclin D1 accumulation and regulates G –S cell-cycle ubiquitously expressed in normal tissues and have four com- 1 progression in a p53-dependent manner by promoting MDM2 mon exons (exons 3–6), which encode a RA domain (1). self-ubiquitination through disruption of the MDM2–DAXX– RASSF1A encodes a 39 kDa peptide containing several HAUSP complex (11, 12). RASSF1A also induces prometaphase domains that are important for its role as a tumor suppressor, arrest through interaction with Cdc20, an activator of the including the C1 zinc finger domain for death receptor asso- anaphase-promoting complex (APC) and consequent blockade ciation, the ataxia telangiectasia mutated phosphorylation site of the APC–Cdc20 interaction (13). RASSF1A also binds to and for DNA damage repair and the SAV/RASSF/HIPPO (SARAH) stabilizes microtubules and controls the tubulin dynamics, domain for association with mammalian sterile 20-like which is intimately related with its capacity to promote cell- kinases, MST1 and MST2 (4, 5). cycle arrest and suppress cell motility (14–16). Although RASSF family members contain a RA domain that potentially associates with the Ras family of GTPase, the ability Department of Life Sciences, Korea University, Seoul, Korea. of most RASSF proteins to associate with Ras has yet to be Note: Supplementary data for this article are available at Cancer Research clearly established. To date, only RASSF2, RASSF4, and RASSF5 Online (http://cancerres.aacrjournals.org/). have been observed to associate directly with K-Ras (17–19). Corresponding Author: Sung-Gil Chi, Department of Life Sciences, School of Contradictory reports of Ras association with RASSF1A lead to Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk- the conjecture that Ras association with RASSF1A might be gu, Seoul 136-701, Republic of Korea (South). Phone: 822-3290-3443; Fax: 822- indirect and most likely mediated through heterodimerization 927-5458; E-mail: [email protected] with RASSF5A (20). Moreover, it is still subject to debate that doi: 10.1158/0008-5472.CAN-15-1752 activeRasisrequiredforRASSF1Atofunctionasatumor Ó2016 American Association for Cancer Research. suppressor and RASSF1A modulates truly the growth inhibitory www.aacrjournals.org 1847 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst January 29, 2016; DOI: 10.1158/0008-5472.CAN-15-1752 Lee et al. response mediated by Ras and that RASSF1A utilizes an as was performed using tissue arrays (SuperBioChips Laboratory) yet unidentified GTPase to provoke its tumor suppression and Vectastain ABC (avidin-biotin-peroxidase) kit (Vector Labo- effects (4, 10). ratories) as described previously (22). To understand the molecular basis of RASSF1A-mediated tumor suppression, we explored the possible involvement of Fluorescence resonance energy transfer analysis RASSF1A in the regulation of Rho family of small GTPase. Here To determine RASSF1A effect on RhoA activation, a fluo- we present evidence that RASSF1A is a novel antagonist of RhoA rescence resonance energy transfer (FRET) assay was per- tumor-promoting activity, which binds directly to active GTP- formed using Raichu-Rhotekin-RBD as a biosensor of active RhoA and facilitates its proteosomal degradation via interaction RhoA (23). The cells were cotransfected with pRaichu-Rho- with Smad ubiquitination regulatory factor 1 (Smurf1) ubiquitin tekin-RBD and either control-RFP or RASSF1A-RFP and trea- E3 ligase. Thus, our study demonstrates a new mechanism by ted with EGF (50 ng/mL) for 3 hours. The FRET measure- which RASSF1A controls multiple processes in RhoA-driven ments were performed on a Zeiss LSM 700 using emission tumor progression. filters for CFP (433 nm excitation, 450/88 nm emission), YFP (433 nm excitation, 585/42 nm emission), and FRET channel Materials and Methods (433 nm excitation, 530/30 nm emission). Quantification of the average FRET/CFP ratio obtained from image data was Human cell lines and tissue specimens analyzed using MetaMorph software (Version 7.5, Molecular Human cancer cell lines (DU145, HCT116, HeLa, A549, and Devices). MDA-MB-231) were purchased from ATCC. IMR-90 cells (human fetal lung fibroblast) were obtained from Korea Cell In vitro translation, binding, and GST pull-down assays Line Bank. All these cell lines were authenticated by short In vitro transcription and translation were carried out using tandem repeat profiling at Korea Cell Line Bank before use. TNT Quick Coupled reticulocyte lysate system (Promega) and Allelic score data revealed a pattern related to the scores biotinylated tRNA molecule (Transcend tRNA, Promega). For reported by the ATCC, and consistent with their presumptive preparation of nucleotide-free RhoA-G14V and RhoA-T19N, identity. A549 (Tet-RASSF1A) cells were generated by cotrans- Flag-RhoA proteins were incubated in nucleotide binding buffer fection of RASSF1A (pcDNA4/TO) and tetracycline repressor and coupled to Flag agarose beads. The complexes were purified vector (pcDNA6/TR; Invitrogen) and selected under blasticidin with 0.1 mol/L glycine buffer. To generate GTPgS or GDP bound (5 mg/mL) and zeocin (100 mg/mL). A total of 60 primary form, nucleotide-free Flag-RhoA proteins were incubated in tumor specimens and their adjacent normal tissues were nucleotide binding buffer containing GTPgS or GDP and 10 obtained by surgical resection in the Kyung Hee University mmol/L MgCl .Purified RASSF1A-V5 was incubated with either Medical Center (Sungbuk-gu, Seoul, Korea). 2 GTPgS-loaded Flag-RhoA-G14V or GDP-loaded Flag-RhoA- T19N and immunoprecipitated with anti-V5 or anti-Flag anti- Expression plasmids and siRNA body. For GST pull-down assay, 1 mgofGTPgS-loaded GST- Expression vectors for wild-type (WT) and deletion mutants RhoA (G14V) was immobilized on GSH beads and incubated of RASSF1A, RhoA, and Smurf1 were constructed using a PCR- with 1 mg of purified Rhotekin-V5 and increasing amounts of based approach. Single amino acid substitution mutants of RASSF1A-V5. RASSF1A and dominant negative (DN) and constitutively active forms of RhoA, Rac1, Cdc42, H-Ras, K-Ras, and N-Ras were generated using the QuickChange site-directed mutagenesis kit Tumor invasion assay (Stratagene). siRNA duplexes against RASSF1A, RhoA, Smurf1, and Cells were plated onto Biocoat Matrigel invasion membranes S100A4 and short hairpin RNA (shRNA) constructs against (BD Biosciences). After 25-hour incubation, the remaining tumor fi RASSF1A and Smurf1 were synthesized by Dharmacon Research cells on the top surface of the lters were removed by wiping with or purchased from Invitrogen. cotton swabs, and the invading cells on the bottom
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