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This study evaluated how YTHDF2 modulates radiotherapy response and underlying mechanisms in rectal cancer. Radioresistant colorectal cancer lines (HCT-116-R, CX-1-R) were generated by cumulative X-ray exposure, followed by YTHDF2 overexpression or knockdown using lentiviral approaches, with radiosensitivity assessed in vitro and in vivo.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ythdf2-alleviates-the-radioresistance-of-rectal-cancer-cells-by-targeting-methylated-myc/373719/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/ythdf2-alleviates-the-radioresistance-of-rectal-cancer-cells-by-targeting-methylated-myc/373719.png","ImageObject",300,407,{"name":92,"@type":93},"Franzy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-02","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the main research question about YTHDF2 and rectal cancer?","Question",{"text":113,"@type":114},"How YTHDF2 affects radiosensitivity of rectal cancer cells and what mechanisms drive that effect.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How were radioresistant colorectal cancer cell lines established?",{"text":118,"@type":114},"HCT-116-R and CX-1-R were generated by accumulative X-ray exposure to induce radioresistance.",{"name":120,"@type":111,"acceptedAnswer":121},"What molecular pathway is implicated in YTHDF2-mediated radiosensitization?",{"text":122,"@type":114},"YTHDF2 is reported to target methylated MYC and modulate the Hippo signaling pathway, enhancing radiosensitivity.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},373719,1790508106,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},2336478945519,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Journal of Radiation Research, Vol. 66, No. 5, 2025, pp. 459–472 [https://doi.org/10.1093/jrr/rraf043](https://doi.org/10.1093/jrr/rraf043)  \nAdvance Access Publication: 27 July 2025  \nYTHDF2 alleviates the radioresistance of rectal cancer cells by targeting methylated MYC  \nYeying Fang 1, 2,†, Shijie Shang3,4,†, Gang Chen5, Dawei Chen 1,4 and  \nJinming Yu 1,4, *  \n1Department of Radiation Oncology, Shandong University Cancer Center, Jiyan Road, Jinan, Shandong 250117, China  \n2Department of Radiation Oncology, First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, Guangxi 530021, China  \n3 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road, Wuhan, Hubei 430030, China  \n4Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road, Jinan, Shandong 250117, China  \n5Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, Guangxi 530021, China  \n*Corresponding author. Department of Radiation Oncology, Shandong University Cancer Center, 440 Jiyan Road, Jinan, Shandong 250117, China.  \nTel: 053187984777; Email: [sdyujinming@126.com](sdyujinming@126.com)  \n†Yeying Fang and Shijie Shang contributed equally to this work.  \n(Received 13 May 2025; revised 17 June 2025; editorial decision 20 June 2025)  \nABSTRACT  \nYTHDF2, aN6-methyladenosine (m6A) recognition protein, is involved in the occurrence and progression of various malignancies. The impact of YTHDF2 on the radiosensitivity of rectal cancer cells remains unclear. This study aimed to investigate the effect and potential mechanisms of YTHDF2 on radiotherapy sensitivity in rectal cancer. Acquired radioresistant colorectal cancer (CRC) cell lines (HCT-116-R and CX-1-R) were established through accumulative X-ray exposure. YTHDF2 was exogenously overexpressed or endogenously knocked down using lentivirus systems, and the radiosensitivity of the cells was analyzed both in vitro and in vivo. High-throughput transcriptome sequencing identified MYC as a downstream target of YTHDF2. RNA stability assays revealed that YTHDF2 facilitated the decay of MYC messenger (mRNA) through an m6A-dependent mechanism. Western blot analyses demonstrated that YTHDF2 modulated MYC expression and the Hippo signaling pathway, enhancing p-MST1/2, p-LATS1 and p-YAP levels while reducing nuclear YAP. Functional assays showed that YTHDF2 overexpression improved radiosensitivity by promoting radiation-induced apoptosis and G2/M phase arrest. MYC overexpression reversed these effects, suggesting a competitive regulatory relationship between YTHDF2 and MYC. These findings indicate that YTHDF2 modulates radiosensitivity through MYC and the Hippo signaling pathway. YTHDF2 enhances the radiosensitivity of rectal cancer cells by facilitating the degradation of MYCmRNA and activating the Hippo signaling pathway. Targeting YTHDF2 may provide a promising therapeutic strategy for overcoming radioresistance in rectal carcinoma.  \nKeywords: YTHDF2; rectal cancer; radioresistance; methylation; MYC; Hippo signaling pathway  \nINTRODUCTION  \nColorectal cancer is the most prevalent type of gastrointestinal cancer and is the third most common cancer worldwide, with rectal cancer accounting for about one-third of all cases [ 1]. Radiotherapy, a medical procedure that uses radiation to kill tumor cells, plays a pivotal role in the treatment of rectal carcinoma. The standard treatment approach for patients with locally advanced rectal carcinoma is a combination of neoadjuvant chemoradiotherapy, followed by total mesorectal excision and adjuvant chemotherapy [2]. However, the response of individuals  \nto radiation varies greatly; only one-third of patients respond completely toneoadjuvant radiation, even in the era of precise radiati","cbCaiaBEDPyooLBt","https://ap.wps.com/l/cbCaiaBEDPyooLBt","pdf",2117128,14,"English","# Abstract\n# Introduction\n## Background: rectal cancer and radiotherapy\n## m6A modification and YTHDF2\n## Study rationale","[{\"question\":\"What is the main research question about YTHDF2 and rectal cancer?\",\"answer\":\"How YTHDF2 affects radiosensitivity of rectal cancer cells and what mechanisms drive that effect.\"},{\"question\":\"How were radioresistant colorectal cancer cell lines established?\",\"answer\":\"HCT-116-R and CX-1-R were generated by accumulative X-ray exposure to induce radioresistance.\"},{\"question\":\"What molecular pathway is implicated in YTHDF2-mediated radiosensitization?\",\"answer\":\"YTHDF2 is reported to target methylated MYC and modulate the Hippo signaling pathway, enhancing radiosensitivity.\"}]","YTHDF2 alleviates the radioresistance of rectal cancer cells by targeting methylated MYC | PDF",1790200297,35]