Transcription of HOTAIR is regulated by RhoC-MRTF-A-SRF signaling pathway in human breast cancer cells

Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

Section: Discussionmentioning

confidence: 99%

Section: Ppi Decreased the Protein Expression Levels Of P65 And Lncrnmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Xiang

Zou

et al. 2018

“…An emerging mechanism underlying the upregulation of HOTAIR in cancer cells is the direct transcriptional activation of HOTAIR by classical oncogenes. For instance, both myocardin-related transcription factor-A, a Rho signaling-responsive co-activator of serum response factor (SRF) governed by the Rho GTPase actin signaling pathway, and SRF could affect HOTAIR expression by regulating HOTAIR gene promoter activity in a CArG box (CC(A/T)6GG sequences)-dependent manner in breast cancer cells [67]. FOXA1 and FOXM1, the 2 members of the forkhead box (FOX) transcription factor family and known to be highly expressed in several cancer types, activated HOTAIR expression in breast cancer [68]; the latter was negatively regulated by estrogen [69].…”

Section: Hotair In Breast Cancermentioning

confidence: 99%

HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer

Tang

Hann

2018

219

135

Long non-coding RNAs (LncRNAs) represent a novel class of noncoding RNAs that are longer than 200 nucleotides without protein-coding potential and function as novel master regulators in various human diseases, including cancer. Accumulating evidence shows that lncRNAs are dysregulated and implicated in various aspects of cellular homeostasis, such as proliferation, apoptosis, mobility, invasion, metastasis, chromatin remodeling, gene transcription, and post-transcriptional processing. However, the mechanisms by which lncRNAs regulate various biological functions in human diseases have yet to be determined. HOX antisense intergenic RNA (HOTAIR) is a recently discovered lncRNA and plays a critical role in various areas of cancer, such as proliferation, survival, migration, drug resistance, and genomic stability. In this review, we briefly introduce the concept, identification, and biological functions of HOTAIR. We then describe the involvement of HOTAIR that has been associated with tumorigenesis, growth, invasion, cancer stem cell differentiation, metastasis, and drug resistance in cancer. We also discuss emerging insights into the role of HOTAIR as potential biomarkers and therapeutic targets for novel treatment paradigms in cancer.

“…LncRNA HOX transcript antisense intergenic RNA (HOTAIR) acts as an oncogene and is aberrantly expressed in multiple types of cancer, and has been considered as predictive factor for poor prognosis in a variety of cancers [65, 66]. HOTAIR regulated multiple signaling and targets via distinct mechanisms, thereby promoting growth and progression of cancer [65, 67].…”

Section: Oncogenic Lncrnasmentioning

confidence: 99%

Functions and Roles of Long-Non-Coding RNAs in Human Nasopharyngeal Carcinoma

Hann²

2018

Nasopharyngeal carcinoma (NPC) is one of the most common cancers originating in the nasopharynx and occurring at high frequency in South-eastern Asia and North Africa. Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNA molecules and key regulators of developmental, physiological, and pathological processes in humans. Emerging studies have shown that lncRNAs play critical roles in tumorgenicity and cancer prognosis. With the development of deep sequencing analyses, an extensive amount of functional lncRNAs have been discovered in nasopharyngeal carcinoma tissues and cell lines. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of NPC are not fully understood. In this review, we briefly illustrate the concept, identification, functional characterization, and summarize recent advancements of biological functions of lncRNAs with heterogeneous mechanistic characterization and their involvement in NPC. Then, we describe individual lncRNAs that have been associated with tumorgenesis, growth, invasion, cancer stem cell differentiation, metastasis, drug resistance and discuss the strategies of their therapeutic manipulation in NPC. We also review the emerging insights into the role of lncRNAs and their potential as biomarkers and therapeutic targets for novel treatment paradigms. Finally, we highlight the up-to-date of clinical information involving lncRNAs and future directions in the linking lncRNAs to potential gene therapies, and how modifications of lncRNAs can be exploited for prevention and treatment of NPC.