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% that is due to an assortment of genomic abnormalities that impedes 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 (HDAC) 1 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.

Human NANOS1 Represses Apoptosis by Downregulating Pro-Apoptotic Genes in the Male Germ Cell Line

“…The three GADD45 (growth arrest and DNA damage inducible 45) protein family members induce apoptosis by binding and activating MAP3K4 kinase, which in turn positively regulates the p38/JNK-mediated apoptotic pathway [21,24]. RHOB (ras homologue family member B), in turn, activates apoptosis by positive regulation of JNK that triggers the activation of pro-apoptotic BCL2L11 [25,26]. We propose that abrogated inhibition of the above-mentioned four pro-apoptotic mRNAs upon expression of mutated NANOS1 accounts for increased apoptosis of TCam-2 cells.…”

Identification of potential biomarkers in cervical cancer with combined public mRNA and miRNA expression microarray data analysis

“…For example, RhoB expression is predictive of an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) response; a EGFR-TKI/Akt inhibitor combination provides a clinical advantage in preventing resistance to EGFR-TKI for RhoB-positive tumor patients ( 26 ). A number of studies have identified a loss of RhoB expression in head, neck, gastric, renal and lung cancer ( 29 – 31 ). Studies of RhoB gene knockout in mice demonstrated that the frequency of chemically induced neoplastic transformation increased, and that the overexpression of RhoB in human cell lines results in the inhibition of signal transduction pathways associated with oncogenesis and tumor survival.…”

A male infertility mutation reverts NANOS1 activity from anti-apoptotic to pro-apoptotic by disrupting repression ofGADD45A,GADD45B,GADD45GandRHOBgenes

“…Moreover, each of the three GADD45 (growth arrest and DNA damage inducible) protein family members induces apoptosis by binding and activating MAP3K4 kinase, which in turn positively regulates p38/JNK cascade [24]. RHOB (ras homolog family member B), on the other hand, activates apoptosis via BCL2L11 BIM activation [25]. Given our obtained results, we propose that lack of repression of above mentioned four pro-apoptotic mRNAs upon expression of p.[(Pro34Thr);(Ser83del)] NANOS1 mutation accounts for increased apoptosis of TCam-2 cells.…”