SLCO4A1-AS1 promotes colorectal tumourigenesis by regulating Cdk2/c-Myc signalling

Abstract

Background SLCO4A1-AS1 was found to be upregulated in several cancer types, including colorectal cancer (CRC). However, the detailed roles of SLCO4A1-AS1 in CRC remain to be elucidated. Therefore, we investigated the functions, mechanism, and clinical significance of SLCO4A1-AS1 in colorectal tumourigenesis. Methods We measured the expression of SLCO4A1-AS1 in CRC tissues using qRT-PCR and determined its correlation with patient prognosis. Promoter methylation analyses were used to assess the methylation status of SLCO4A1-AS1. Gain- and loss-of-function assays were used to evaluate the effects of SLCO4A1-AS1 on CRC growth in vitro and in vivo. RNA pull-down, RNA immunoprecipitation, RNA-seq, luciferase reporter and immunohistochemistry assays were performed to identify the molecular mechanism of SLCO4A1-AS1 in CRC. Results SLCO4A1-AS1 was frequently upregulated in CRC tissues based on multiple CRC cohorts and was associated with poor prognoses. Aberrant overexpression of SLCO4A1-AS1 in CRC is partly attributed to the DNA hypomethylation of its promoter. Ectopic SLCO4A1-AS1 expression promoted CRC cell growth, whereas SLCO4A1-AS1 knockdown repressed CRC proliferation both in vitro and in vivo. Mechanistic investigations revealed that SLCO4A1-AS1 functions as a molecular scaffold to strengthen the interaction between Hsp90 and Cdk2, promoting the protein stability of Cdk2. The SLCO4A1-AS1-induced increase in Cdk2 levels activates the c-Myc signalling pathway by promoting the phosphorylation of c-Myc at Ser62, resulting in increased tumour growth. Conclusions Our data demonstrate that SLCO4A1-AS1 acts as an oncogene in CRC by regulating the Hsp90/Cdk2/c-Myc axis, supporting SLCO4A1-AS1 as a potential therapeutic target and prognostic factor for CRC.

Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer

“…The identified number of lncRNA increased rapidly with the progress of RNA sequencing technology. In our previous studies, we screened and identified several tumorrelated lncRNAs in CRC using microarrays [7][8][9][10][11][12][13][14][15]. In this study, we further screened CRC-related lncRNAs using next-generation sequencing and identified a cancer-promoting lncRNA, DLGAP1-AS2, is upregulated in many types of cancers.…”

“…We extensively analyzed the differentially expressed lncRNAs in the CRC genome and characterized a series of CRC-related lncRNAs, including FEZF1-AS1, LINC00152 ( CYTOR ), MCM3AP-AS1, SLCO4A1-AS1, SNHG6, SNHG15, SHNG17 and UCA1 [7][8][9][10][11][12][13][14][15]. For example, we showed that FEZF1-AS1 promotes CRC tumorigenesis and progression by regulating PKM2/ STAT3 signaling and glycolysis [7].…”

A review on the role of cyclin dependent kinases in cancers

“…These observations have been associated with advanced tumor stage and grade [105]. In NOD/SCID mice 4-AAQB treatment: ↓ tumor growth via suppressing CDK2 and CDK4 [111] female BALB/c mice ∆ Lnc712: ↓ tumor growth Via suppressing CDK2 [116] female NOD/SCID mice ALT + PD combination: ↓ tumor growth via inhibiting both cdk4 and cdk2 [117] female BALB/c nude mice Higenamine and cucurbitacin B: ↓ tumor growth via suppressing the interaction of AKT and CDK2 [120] 5-6-week old female athymic nu/nu mice CDK2/9 inhibitors, CYC065 and eribulin combination: ↓ tumor volume [124] Cervical cancer 4-week-old BALB/C nude mice ∆ hsa_circ_0000520: ↓ tumor volume and weight [128] 4-6-week-old female BALB/c nude mice ∆ circZFR: ↓ tumor growth [130] Cholangiocarcinoma 6-week old NSG mice Dinaciclib and gemcitabine combination: ↓ tumor growth [132] Colorectal cancer nude mice ↑↑ NPTX1: ↓ tumor growth via downregulating CDK2 [133] 8-10-week-old SCID mice Dual CDK2/9 inhibition: ↓ tumor growth [136] 5-week-old athymic nude BALB/c mice ∆ SLCO4A1-AS1: ↓ tumor growth [137] Gastric cancer 4-6-week-old nude BALB/c mice ∆ LINC01021: ↓ tumor volume and weight [139] Glioma 6-week-old male BALB/c mice ∆ LINC00958: ↓ tumor growth [142] male BALB/c nude mice ∆ HSP90AA1-IT1: ↓ tumor growth [143] Hepatocellular carcinoma 4-week-old female BALB/c-nu, nude mice ∆ HNRNPU: ↓ tumor volume and weight [145] 6-8-week-old male BALB/C nude mice ∆ OLA1: ↓ tumor growth and weight [148] Nude mice ↑↑ TPT1-AS1: ↓ tumor growth [149] 4-week-old athymic BALB/c mice ↑↑ miR-155: ↑ tumor weight [153] Lung cancer 6-8-week-old male immunocompetent 129S2/ SVPasCrl mice CDK2/9 inhibitor, CCT68127: ↓ tumor growth [157] BALB/c athymic nude mice PROS reduced tumor volumes and weights via inhibiting STAT3/ VEGF/ CDK2 axis [158] Medulloblastoma 6-8-week-old female Athymic Nude-Foxn1nu mice BET bromodomain inhibition and CDK2 inhibition: ↓ tumor growth [160] breast cancer, up-regulation of MTHFD2, which contributes in the cell cycle through binding to CDK2, has been associated with shorter OS, tumor grade and stage [107].…”

Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy

“…SLCO4A1-AS1 can activate the EGFR/MAPK pathway [ 153 ], and also inhibit the degradation of β-catenin and increase the activation of the Wnt/β-catenin signaling pathway [ 154 ]. Moreover, SLCO4A1-AS1 has been reported to increase the level of CDK2 by enhancing the interaction between CDK2 and heat-shock protein 90 (HSP90), activating the c-MYC signaling pathway [ 155 ].…”