ALKBH5 Facilitates Hypoxia-Induced Paraspeckle Assembly and IL8 Secretion to Generate an Immunosuppressive Tumor Microenvironment

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 23; pp. 5876 - 5888
• Main Authors: Dong, Feng, Qin, Xiaoyang, Wang, Baofeng, Li, Qian, Hu, Jinyang, Cheng, Xuan, Guo, Dongsheng, Cheng, Fangling, Fang, Chuan, Tan, Yanli, Yan, Han, He, You, Sun, Xiaoyu, Yuan, Ye, Liu, Hang, Li, Ting, Zhao, Yingying, Kang, Chunsheng, Wu, Xudong
• Format: Journal Article
• Language: English
• Published: United States 01.12.2021
• Subjects: AlkB Homolog 5, RNA Demethylase - genetics; AlkB Homolog 5, RNA Demethylase - metabolism; Animals; Apoptosis; Cell Proliferation; DNA Methylation; Gene Expression Regulation, Neoplastic; Glioblastoma - immunology; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Immunosuppressive Agents; Interleukin-8 - genetics; Interleukin-8 - metabolism; Male; Mice; Mice, Inbred C57BL; Paraspeckles - immunology; Paraspeckles - metabolism; Paraspeckles - pathology; Tumor Cells, Cultured; Tumor Microenvironment; Tumor-Associated Macrophages - immunology; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-21-1456

The dynamic changes of RNA N6-methyl-adenosine (m A) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer cell m A dynamics in the hypoxic tumor niche and its pathological consequences in glioblastoma multiforme (GBM). The m A demethylase ALKBH5 was induced in GBM models under hypoxic conditions and was associated with a hypoxic gene signature in GBM patient samples. Depletion or inactivation of ALKBH5 in GBM cells significantly suppressed hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in allograft tumors. Expression and secretion of CXCL8/IL8 were significantly suppressed in ALKBH5-deficient tumors. However, ALKBH5 did not regulate CXCL8 m A directly. Instead, hypoxia-induced ALKBH5 erased m A deposition from the lncRNA NEAT1, stabilizing the transcript and facilitating NEAT1-mediated paraspeckle assembly, which led to relocation of the transcriptional repressor SFPQ from the CXCL8 promoter to paraspeckles and, ultimately, upregulation of CXCL8/IL8 expression. Accordingly, ectopic expression of CXCL8 in ALKBH5-deficient GBM cells partially restored TAM recruitment and tumor progression. Together, this study links hypoxia-induced epitranscriptomic changes to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. SIGNIFICANCE: Hypoxia induces tumor immune microenvironment remodeling through an ALKBH5-mediated epigenetic and epitranscriptomic mechanism, providing potential immunotherapeutic strategies for treating glioblastoma.