title: RhoB upregulation leads to either apoptosis or cytostasis through differential target selection.
abstract: Anaplastic thyroid carcinoma is a highly aggressive undifferentiated carcinoma with a mortality rate near 100% due to an assortment of genomic abnormalities which impede the success of therapeutic options. Our laboratory has previously identified that RhoB upregulation serves as a novel molecular therapeutic target and agents upregulating RhoB combined with paclitaxel lead to antitumor synergy. Knowing that histone deacetylase 1 (HDAC1) transcriptionally suppresses RhoB, we sought to extend our findings to other HDACs and to identify the HDAC inhibitor (HDACi) that optimally synergize with paclitaxel. Here we identify HDAC6 as a newly discovered RhoB repressor. By using isoform selective HDAC inhibitors (HDACi) and shRNAs, we show that RhoB has divergent downstream signaling partners, which are dependent on the HDAC isoform that is inhibited. When RhoB upregulates only p21 (cyclin kinase inhibitor) using a class I HDACi (romidepsin), cells undergo cytostasis. When RhoB upregulates BIMEL using class II/(I) HDACi (belinostat or vorinostat), apoptosis occurs. Combinatorial synergy with paclitaxel is dependent upon RhoB and BIMEL while upregulation of RhoB and only p21 blocks synergy. This bifurcated regulation of the cell cycle by RhoB is novel and silencing either p21 or BIMEL turns the previously silenced pathway on, leading to phenotypic reversal. This study intimates that the combination of belinostat/vorinostat with paclitaxel may prove to be an effective therapeutic strategy via the novel observation that class II/(I) HDACi antagonize HDAC6-mediated suppression of RhoB and subsequent BIMEL, thereby promoting antitumor synergy. These overall observations may provide a mechanistic understanding of optimal therapeutic response.
authors.affiliation: Departments of Cancer BiologyInternal MedicineDivision of EndocrinologyEndocrine Malignancy Working GroupMayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Marlow
authors.affiliation: Departments of Cancer BiologyInternal MedicineDivision of EndocrinologyEndocrine Malignancy Working GroupMayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Ilah
authors.initials: I
authors.lastname: Bok
authors.affiliation: Departments of Cancer BiologyInternal MedicineDivision of EndocrinologyEndocrine Malignancy Working GroupMayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA Departments of Cancer BiologyInternal MedicineDivision of EndocrinologyEndocrine Malignancy Working GroupMayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA Departments of Cancer BiologyInternal MedicineDivision of EndocrinologyEndocrine Malignancy Working GroupMayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Smallridge
authors.affiliation: Departments of Cancer BiologyInternal MedicineDivision of EndocrinologyEndocrine Malignancy Working GroupMayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA Departments of Cancer BiologyInternal MedicineDivision of EndocrinologyEndocrine Malignancy Working GroupMayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA copland.john@mayo.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000077337:Vorinostat; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013449:Sulfonamides; D000077337:Vorinostat; C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020743:rhoB GTP-Binding Protein; C487081:belinostat; D017239:Paclitaxel
keywords: BIM; HDAC; RhoB; anaplastic thyroid carcinoma; p21