RhoB upregulation leads to either apoptosis or cytostasis through differential target selection

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 BIM<inf>EL</inf> using class II/(I) HDACi (belinostat or vorinostat), apoptosis occurs. Combinatorial synergy with paclitaxel is dependent upon RhoB and BIM<inf>EL</inf> 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 BIM<inf>EL</inf> 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 BIM<inf>EL</inf>, thereby promoting antitumor synergy. These overall observations may provide a mechanistic understanding of optimal therapeutic response.

Original languageEnglish (US)
Pages (from-to)777-792
Number of pages16
JournalEndocrine-Related Cancer
Volume22
Issue number5
DOIs
StatePublished - Oct 1 2015

Fingerprint

Histone Deacetylase Inhibitors
Paclitaxel
Up-Regulation
Apoptosis
Protein Isoforms
Histone Deacetylase 1
Cyclin-Dependent Kinase Inhibitor p21
Therapeutics
Cell Cycle
Observation
Carcinoma
Mortality

Keywords

  • Anaplastic thyroid carcinoma
  • BIM
  • HDAC
  • P21
  • RhoB

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

RhoB upregulation leads to either apoptosis or cytostasis through differential target selection. / Marlow, Laura A.; Bok, Ilah; Smallridge, Robert Christian; Copland, John A III.

In: Endocrine-Related Cancer, Vol. 22, No. 5, 01.10.2015, p. 777-792.

Research output: Contribution to journalArticle

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