ALKBH5 in Colorectal Cancer: An Insufficiently Explored and Controversial Research Area

With interest we read the contribution of Zhai et al1Zhai J. et al.Gastroenterology. 2023; 165: 445-462Abstract Full Text Full Text PDF PubMed Google Scholar on the AlkB homolog 5 (ALKBH5) as a promising prognostic factor and therapeutic target for patients with colorectal cancer (CRC). We congratulate the authors and would like to discuss some points about the role of ALKBH5 on CRC. In their article, the authors found that ALKBH5 is associated with poor prognosis in patients with CRC. They further showed that ALKBH5 expression in CRC recruits immune-suppressive myeloid-derived suppressor cells, which in turn suppresses infiltration of antitumor CD8+ T and natural killer cells. Targeting ALKBH5 reactivates antitumor immunity and synergizes with anti-PD1 immune checkpoint blockade therapy to inhibit CRC growth. Shen et al2Shen D. et al.Clin Transl Med. 2023; 13: e1279Crossref PubMed Google Scholar showed that ALKBH5 was significantly up-regulated in CRC tissues and could facilitate the proliferation and motility of CRC cells. That indicated that inhibition of ALKBH5 could be an attractive target to prevent CRC. However, Luo et al3Luo J. et al.Clin Transl Oncol. 2023; 25: 2265-2276Crossref PubMed Scopus (5) Google Scholar demonstrated that ALKBH5 was down-regulated in CRC and that ALKBH5 overexpression promoted reactive oxygen species release and ferroptosis, resulting in mitigated tumor growth in vivo. Moreover, Yang et al4Yang P. et al.Pathol Oncol Res. 2020; 26: 1615-1623Crossref PubMed Scopus (50) Google Scholar revealed that ALKBH5 significantly inhibits tumor progression and serves as a potential therapeutic target for colon cancer. In addition, accumulating evidence reveals that ALKBH5 plays a crucial tumor-suppressive role in CRC.5Zhang Z. et al.Clin Transl Med. 2022; 12: e940Crossref PubMed Google Scholar, 6Wu X. et al.Am J Transl Res. 2021; 13: 11209-11222PubMed Google Scholar, 7Ge J. et al.Transl Oncol. 2023; 34101683Crossref PubMed Scopus (0) Google Scholar, 8Ye M. et al.Int J Biol Sci. 2023; 19: 3115-3127Crossref PubMed Scopus (4) Google Scholar In this regard, we put forward our view that the role of ALKBH5 in CRC is controversial and needs further elucidation. Is the effect of ALKBH5 on the CRC oncogenic or tumor suppressive? In conclusion, ALKBH5 is involved in the development of CRC, but its role and specific mechanism remain controversial. Furthermore, more basic research is required to further clarify the role of ALKBH5 in CRC. We hope that Zhai et al will find our queries of interest for further experimental research on the field. ALKBH5 Drives Immune Suppression Via Targeting AXIN2 to Promote Colorectal Cancer and Is a Target for Boosting ImmunotherapyGastroenterologyVol. 165Issue 2PreviewALKBH5 promotes colorectal tumorigenesis by promoting immune suppression via an m6A–AXIN2–DKK1 axis. ALKBH5 is a potential therapeutic target for patients with colorectal cancer. Full-Text PDF Open AccessReplyGastroenterologyVol. 165Issue 6PreviewWe appreciate the comments by Yang and Zhang1 on our study showing that ALKBH5 promotes colorectal cancer (CRC) progression through modulation of antitumor immunity. We applaud various efforts by other investigators to determine the potential role of ALKBH5 in CRC, some of which conclude that ALKBH5 functions as a crucial tumor suppressor.2–6 Full-Text PDF