m(6) A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal types of malignant tumors worldwide. Epitranscriptome, such as N6 -methyladenosine (m6 A) of mRNA, is an abundant post-transcriptional mRNA modification and has been recently implicated to play roles in several cancers, whereas the significance of m6 A modifications is virtually unknown in ESCC. Analysis of tissue microarray of the tumors in 177 ESCC patients showed that higher expression of m6 A demethylase ALKBH5 correlated with poor prognosis and that ALKBH5 was an independent prognostic factor of the survival of patients. There was no correlation between the other demethylase FTO and prognosis. siRNA knockdown of ALKBH5 but not FTO significantly suppressed proliferation and migration of human ESCC cells. ALKBH5 knockdown delayed progression of cell cycle and accumulated the cells to G0/G1 phase. Mechanistically, expression of CDKN1A (p21) was significantly up-regulated in ALKBH5-depleted cells, and m6 A modification and stability of CDKN1A mRNA were increased by ALKBH5 knockdown. Furthermore, depletion of ALKBH5 substantially suppressed tumor growth of ESCC cells subcutaneously transplanted in BALB/c nude mice. Collectively, we identify ALKBH5 as the first m6 A demethylase that accelerates cell cycle progression and promotes cell proliferation of ESCC cells, which is associated with poor prognosis of ESCC patients.

Nagaki Y ，Motoyama S ，Yamaguchi T ，Hoshizaki M ，Sato Y ，Sato T ，Koizumi Y ，Wakita A ，Kawakita Y ，Imai K ，Nanjo H ，Watanabe H ，Imai Y ，Minamiya Y ，Kuba K ... -  《-》

m(6)A demethylase ALKBH5 suppression contributes to esophageal squamous cell carcinoma progression.

Xiao D ，Fang TX ，Lei Y ，Xiao SJ ，Xia JW ，Lin TY ，Li YL ，Zhai JX ，Li XY ，Huang SH ，Jia JS ，Tian YG ，Lin XL ，Cai KC ，Sun Y ... -  《Aging-US》

ALKBH5 Is Lowly Expressed in Esophageal Squamous Cell Carcinoma and Inhibits the Malignant Proliferation and Invasion of Tumor Cells.

Modification of N6-methyladenosine (m6A) and RNA m6A regulatory factors is required in cancer advancement. The contribution of m6A and its alteration in esophageal squamous cell carcinoma (ESCC) is still unclear. ALKBH5 was lowly expressed in ESCC tissues, which the total m6A level was increased in ESCC tissue than the presentation in normal healthy tissue. The pcDNA3.1-ALKBH5 recombinant plasmid was transfected into KYSE-150 and Eca-109 cells. The overexpression of ALKBH5 is responsible for a significant reduction of the total m6A levels in Eca-109 and KYSE150 cells, inhibiting the proliferation capability, migration, and cell invasion. ALKBH5 as a demethylase was lowly expressed in cancer progression of ESCC and acts as a crucial component in ESCC progression.

Li J ，Liu H ，Dong S ，Zhang Y ，Li X ，Wang J ... -  《-》

N(6)-methyladenosine ALKBH5 promotes non-small cell lung cancer progress by regulating TIMP3 stability.

Mounting evidence demonstrates that N6-methyladenosine (m6A) play critical roles of m6A in the epigenetic regulation, especially for human cancer. The m6A modification is installed by methyltransferase and erased demethylases, leading to the significant modification for gene expression and cell fate. Here, we investigated the biological roles and mechanism of demethylase alkylation repair homolog protein 5 (ALKBH5) in the non-small cell lung cancer (NSCLC). Results revealed that ALKBH5 was ectopically up-regulated in the NSCLC tissue and cells, and closely correlated with the poor prognosis. Functionally, ALKBH5 promoted the proliferation and reduced apoptosis of NSCLC cells in vitro, and knockdown of ALKBH5 repressed the tumor growth in vivo. Mechanistically, RNA immunoprecipitation sequencing (RIP-Seq) revealed that ALKBH5 targeted the TIMP3. Moreover, ALKBH5 repressed TIMP3 mRNA stability and protein production. In conclusion, the present research confirmed the ALKBH5/TIMP3 pathway in the NSCLC oncogenesis progress, providing a novel insight for the epitranscriptome and potential therapeutic target for NSCLC.

Zhu Z ，Qian Q ，Zhao X ，Ma L ，Chen P ... -  《-》

RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma.

Long non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation and progression of esophageal squamous cell carcinoma (ESCC). N6-methyladenosine (m6A) modification now is recognized as a master driver of RNA function to maintain homeostasis in cancer cells. However, how m6A regulates LncRNA function and its role in tumorigenesis of ESCC remain unclear. Multiple ESCC datasets were used to analyze gene expression in tumor tissues and normal tissues. Kaplan-Meier method and the ROC curve were conducted to evaluate the prognostic value and diagnostic value of LINC00022 in ESCC, respectively. Both gain-of-function and loss-of-function experiments were employed to investigate the effects of LINC00022 on ESCC growth in vitro and in vivo. Bioinformatics analysis, colorimetric m6A assay, RIP, MeRIP and co-IP was performed to explore the epigenetic mechanism of LINC00022 up-regulation in ESCC. Here we report that m6A demethylation of LncRNA LINC00022 by fat mass and obesity-associated protein (FTO) promotes tumor growth of ESCC in vivo. Clinically, we revealed that LINC00022 was up-regulated in primary ESCC samples and was predictive of poor clinical outcome for ESCC patients. Mechanistically, LINC00022 directly binds to p21 protein and promotes its ubiquitination-mediated degradation, thereby facilitating cell-cycle progression and proliferation. Further, the elevated FTO in ESCC decreased m6A methylation of LINC00022 transcript, leading to the inhibition of LINC00022 decay via the m6A reader YTHDF2. Over-expression of FTO was shown to drive LINC00022-dependent cell proliferation and tumor growth of ESCC. Thus, this study demonstrated m6A-mediated epigenetic modification of LncRNA contributes to the tumorigenesis in ESCC and LINC00022, specific target of m6A, serves as a potential biomarker for this malignancy.

Cui Y ，Zhang C ，Ma S ，Li Z ，Wang W ，Li Y ，Ma Y ，Fang J ，Wang Y ，Cao W ，Guan F ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》