KDM2B mediates the Wnt/β-catenin pathway through transcriptional activation of PKMYT1 via microRNA-let-7b-5p/EZH2 to affect the development of non-small cell lung cancer.

The significance of KDM2B in oncogenesis has been appreciated, but the mechanism behind is incompletely understood. In this work, we addressed its effects on the progression of non-small cell lung cancer (NSCLC). Overexpression of KDM2B was linked to dismal prognoses of NSCLC patients. Based on the expression levels of KDM2B in a panel of NSCLC cell lines, A549, showing lower level of expression, and SK-MES-1, showing higher levels of expression, were selected as model systems to evaluate the effect of KDM2B overexpression and KDM2B silencing, respectively. Knockdown of KDM2B hampered NSCLC cell proliferation, invasion, as well as migration, while enhanced apoptosis. Additionally, KDM2B repressed the expression of microRNA (miR)-let-7b-5p through demethylation modification of H3K36me2, thereby promoting the expression of zester homolog 2 (EZH2), the target gene of let-7b-5p in NSCLC. Moreover, EZH2 transcriptionally induced the expression of PKMYT1 to activate the Wnt/β-catenin pathway. Sh-EZH2 and sh-PKMYT1 neutralized the supporting effects of KDM2B on cell proliferation, invasion and migration. Additionally, deletion of KDM2B reduced the xenograft volumes in nude mice. In conclusion, KDM2B induces the EZH2/PKMYT1/Wnt/β-catenin axis by inhibiting the let-7b-5p expression, which promotes NSCLC growth. More investigations are essential to determine the oncogenic role of KDM2B in NSCLC.

Zhang X ，Yin Z ，Li C ，Nie L ，Chen K ... -  《-》

Inhibition of microRNA let-7b expression by KDM2B promotes cancer progression by targeting EZH2 in ovarian cancer.

MicroRNA let-7b is a potent tumor suppressor and targets crucial oncogenes. Previous studies have shown that let-7b expression is suppressed in ovarian cancer; however, the regulatory mechanisms of let-7b in ovarian cancer are still not well defined. The cellular role and targets of let-7b in ovarian cancer remain elusive. In the present study, we showed that histone demethylase, KDM2B, directly suppressed let-7b expression by H3K36me2 demethylation. Moreover, let-7b inhibited EZH2 expression in ovarian cancer cells. Based on these results we know that let-7b antagonizes the enhancement of EZH2 expression caused by KDM2B overexpression, and its expression is negatively correlated with KDM2B and EZH2 expression. More importantly, proliferation, migration, and wound healing assays showed that let-7b inhibited ovarian cancer cell proliferation and migration in vitro. Additionally, let-7b overexpression neutralized KDM2B-promoted cell proliferation and migration. Furthermore, downregulation of let-7b increased the xenografted tumor volumes in nude mice that were transplanted with KDM2B-silenced cells. EZH2 silencing reversed the tumor growth enhancement mediated by inhibition of let-7b. Last, we show that let-7b expression is suppressed in ovarian carcinomas and its expression is negatively associated with the clinicopathological features of ovarian cancer, including histological type, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastatic status. In conclusion, in ovarian cancer, let-7b expression is epigenetically suppressed by high expression of KDM2B. The loss of let-7b upregulates the expression of EZH2, which promotes ovarian cancer growth in vitro and in vivo.

Kuang Y ，Xu H ，Lu F ，Meng J ，Yi Y ，Yang H ，Hou H ，Wei H ，Su S ... -  《-》

LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway.

Non-small cell lung cancer (NSCLC) is the most common type of human lung cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies have been achieved. Bioinformatics methods were used to identify differential long non-coding RNA expression in NSCLC. Real-time RT-PCR experiments were used to examine the expression pattern of lncRNA PKMYT1AR, miR-485-5p. Both in vitro and in vivo functional assays were performed to investigate the functional role of PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating cell proliferation, migration and tumor growth. Dual luciferase reporter assay, fluorescent in situ hybridization (FISH), immunoblot, co-immunoprecipitation experiments were used to verify the molecular mechanism. Here, we identify a human-specific long non-coding RNA (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that is induced in NSCLC by Yin Yang 1 (YY1) factor, especially in cancerous cell lines (H358, H1975, H1299, H1650, A549 and SPC-A1) compared to that in normal human bronchial epithelium cell line (BEAS-2B). We show that PKMYT1AR high expression correlates with worse clinical outcome, and knockdown of PKMYT1AR inhibits tumor cell proliferation, migration and xenograft tumor formation abilities. Bioinformatic analysis and a luciferase assay demonstrate that PKMYT1AR directly interacts with miR-485-5p to attenuate the inhibitory role on its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) in NSCLC. Furthermore, we uncover that miR-485-5p is downregulated in both cancerous cell lines and peripheral blood serum isolated from NSCLC patients compared to reciprocal control groups. Consistently, forced expression of miR-485-5p inhibits the proliferation and migration abilities of tumor cells. Moreover, we provide evidence showing that PKMYT1AR targeting antisense oligonucleotide (ASO) dramatically inhibit tumor growth in vivo. Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting β-TrCP1 mediated ubiquitin degradation of β-catenin proteins, which in turn causes enhanced tumorigenesis. Our findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.

He Y ，Jiang X ，Duan L ，Xiong Q ，Yuan Y ，Liu P ，Jiang L ，Shen Q ，Zhao S ，Yang C ，Chen Y ... -  《Molecular Cancer》

The KDM2B- let-7b -EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy.

Karoopongse E ，Yeung C ，Byon J ，Ramakrishnan A ，Holman ZJ ，Jiang PY ，Yu Q ，Deeg HJ ，Marcondes AM ... -  《PLoS One》

Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells.

Tzatsos A ，Paskaleva P ，Lymperi S ，Contino G ，Stoykova S ，Chen Z ，Wong KK ，Bardeesy N ... -  《-》