lncRNA HOXD-AS1 Regulates Proliferation and Chemo-Resistance of Castration-Resistant Prostate Cancer via Recruiting WDR5

Abstract

Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival. Knockdown of HOXD-AS1 inhibited the proliferation and chemo-resistance of CRPC cells in vitro and in vivo. Furthermore, we identified several cell cycle, chemo-resistance, and castration-resistance-related genes, including PLK1, AURKA, CDC25C, FOXM1, and UBE2C, that were activated transcriptionally by HOXD-AS1. Further investigation revealed that HOXD-AS1 recruited WDR5 to directly regulate the expression of target genes by mediating histone H3 lysine 4 tri-methylation (H3K4me3). In conclusion, our findings indicate that HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance in prostate cancer by recruiting WDR5. This sheds a new insight into the regulation of CRPC by lncRNA and provides a potential approach for the treatment of CRPC.

Silencing of long noncoding RNA HOXD‐AS1 inhibits proliferation, cell cycle progression, migration and invasion of hepatocellular carcinoma cells through MEK/ERK pathway

“…Here, we also showed that HOXD-AS1 was also overexpressed in HCC tissues and relevant to the histologic grade based on TCGA data and experimental validation. 21 Whereas in non-small cell lung cancer, silencing of HOXD-AS1 could largely give rise to the cell cycle arrest of G0/G1 stage in A549 cells, 22 indicating there might be differences in the roles and mechanism of action of HOXD-AS1 among different types of cancer. For example, HOXD-AS1 has been demonstrated to competitively bind with microRNA such as miR-19a and miR-130a-3p to accelerate metastasis.…”

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

“…The chemosensitivity assay and apoptosis analysis were performed as described previously (23)(24)(25) and as detailed in the Supplementary Materials and Methods section. Caspase-3/7 activity was measured using a Caspase-Glo 3/7 Assay kit (Promega) as previously described (23,24).…”

“…Caspase-3/7 activity was measured using a Caspase-Glo 3/7 Assay kit (Promega) as previously described (23,24). The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was conducted using the In Situ Cell Death Detection Kit (Roche), following the manufacturer's instructions and as described previously (25).…”

“…RNA isolation and qRT-PCR were performed as previously described (25,27). Relative expression was calculated using the 2 ÀDDCt method (Ct, cycle threshold).…”

A prognostic 10‐lncRNA expression signature for predicting the risk of tumour recurrence in breast cancer patients

“…21 HAGLR, also known as HOXD-as1, was involved in the occurrence and progression of variate types of human tumours, including bladder cancer, hepatocellular carcinoma, prostate cancer, gastric cancer, neuroblastoma and lung cancer. [25][26][27][28][29][30][31] In prostate cancer, HOXD-AS1 recruited WDR5 to mediate histone H3 lysine 4 tri-methylation, thus promoting cell proliferation, chemo-resistance and castration resistance. 28 In ovarian cancer, HOXD-AS1 was reported to competitively bind to miR-608 to regulate the expression of frizzled family receptor 4 (FZD4) and to enhance proliferation, migration and invasion capabilities of ovarian cancer cells.…”