Inhibition of PRMT5-mediated regulation of DKK1 sensitizes colorectal cancer cells to chemotherapy

• Published in: Cellular signalling Vol. 119; p. 111166
• Main Authors: Abumustafa, Wafaa, Castven, Darko, Becker, Diana, Salih, Shahenaz Shaban, Manzoor, Shaista, Zamer, Batoul Abi, Talaat, Iman, Hamad, Mawieh, Marquardt, Jens Uwe, Muhammad, Jibran Sualeh
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.07.2024
• Subjects: Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DKK1; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; KRAS mutation; PRMT5; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; PRMT5; KRAS mutation; DKK1; Doxorubicin; Colorectal cancer
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2024.111166

The Dickkopf family proteins (DKKs) are strong Wnt signaling antagonists that play a significant role in colorectal cancer (CRC) development and progression. Recent work has shown that DKKs, mainly DKK1, are associated with the induction of chemoresistance in CRC and that DKK1 expression in cancer cells correlates with that of protein arginine N-methyltransferase 5 (PRMT5). This points to the presence of a regulatory loop between DKK1 and PRMT5. Herein, we addressed the question of whether PRMT5 contributes to DKK1 expression in CRC and hence CRC chemoresistance. Both in silico and in vitro approaches were used to explore the relationship between PRMT5 and different DKK members. Our data demonstrated that DKK1 expression is significantly upregulated in CRC clinical samples, KRAS-mutated CRC in particular and that the levels of DKK1 positively correlate with PRMT5 activation. Chromatin immunoprecipitation (ChIP) data indicated a possible epigenetic role of PRMT5 in regulating DKK1, possibly through the symmetric dimethylation of H3R8. Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth. [Display omitted] •PRMT5 regulates DKK1 in KRAS-mutated CRC, impacting chemoresistance.•DKK1 expression correlates with PRMT5 in clinical CRC samples.•Chromatin immunoprecipitation reveals PRMT5's epigenetic role.•Targeting DKK1 or PRMT5 inhibition synergizes with doxorubicin.