AUTHOR=Pan Weijie , Wang Kaijing , Li Jiayong , Li Hanhua , Cai Yuchan , Zhang Min , Wang Aili , Wu Yazhou , Gao Wei , Weng Wenhao 

TITLE=Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.771528

DOI=10.3389/fonc.2021.771528

ISSN=2234-943X

ABSTRACT=<p>Emerging evidence suggests that hypermethylation of <italic>HOXD10</italic> plays an important role in human cancers. However, the biological and clinical impacts of <italic>HOXD10</italic> overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of <italic>HOXD10</italic> in paired cancer and normal tissues (<italic>n</italic> = 42) by using pyrosequencing, followed by validation of the methylation status of <italic>HOXD10</italic> from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of <italic>HOXD10</italic> was characterized in cell lines. We further evaluated the effects of <italic>HOXD10</italic> and its targets on chemoresistance in our established resistant cell lines and clinical cohort (<italic>n</italic> = 66). <italic>HOXD10</italic> was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, <italic>HOXD10</italic> acts as a tumor suppressor gene, in which <italic>HOXD10</italic>-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the <italic>HOXD10</italic> promoter, and demethylation by 5-Aza-2′-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce <italic>HOXD10</italic> expression. <italic>HOXD10</italic> regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of <italic>HOXD10</italic> in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that <italic>HOXD10</italic> is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of <italic>HOXD10</italic> activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).</p>