# LncRNA Dlx4os drives malignant transformation and phenotype switching in melanoma **Authors:** Ana Luisa Pedroso Ayub, Beatriz Cristina Biz Tonin, Hátylas Azevedo, Pedro Henrique Fogaça Jordão, Tanvi Saxena, Leinal Sejour, Jeremie Nsengimana, Ioannis Vlachos, Eduardo Moraes Reis, Frank John Slack, Miriam Galvonas Jasiulionis PMC · DOI: 10.1080/15592294.2026.2641924 · 2026-03-19 ## TL;DR This study shows that the lncRNA Dlx4os promotes melanoma aggressiveness and plasticity, making it a potential target for treatment. ## Contribution The study identifies Dlx4os as a novel lncRNA regulator of melanoma phenotypic switching and malignant transformation. ## Key findings - Dlx4os knockdown reduces melanoma cell invasiveness and promotes a differentiated phenotype. - Dlx4os regulates key phenotypic state markers like Sox10, Mitf, and Tgfβ. - A human orthologue of Dlx4os was identified, suggesting translational potential. ## Abstract Cutaneous melanoma, a highly aggressive and therapy-resistant skin cancer, is characterized by its remarkable cellular plasticity, enabling tumour cells to switch between different phenotypic states. This plasticity contributes to tumour heterogeneity and is regulated by key transcription factors. Long non-coding RNAs (lncRNAs) are emerging as crucial regulators in melanoma progression, yet much remains to be explored regarding their role in phenotype switching. In this study, we analysed long non-coding RNAs (lncRNAs) across different murine melanoma cell lines, identifying a set of lncRNAs potentially involved in regulating melanoma phenotypic state through cis-regulation of neighbouring protein-coding genes. We demonstrated that the lncRNA Dlx4os regulates genes associated with melanoma plasticity, favouring a mesenchymal-like, undifferentiated state. Dlx4os knockdown redirected melanoma cells to a more differentiated and less malignant phenotype, confirmed by differential expression of phenotypic state markers (Sox10, Mitf, Tgfβ, Sox6, Mlana), reduced their invasive and migratory potential, and delayed tumour progression in vivo. Furthermore, we identified a human orthologue of Dlx4os. Our findings highlight the potential of Dlx4os as both a biomarker and therapeutic target, capable of modulating melanoma’s phenotypic plasticity to influence treatment response and metastasis. ## Linked entities - **Genes:** Dlx4os (distal-less homeobox 4, opposite strand) [NCBI Gene 320453], SOX10 (SRY-box transcription factor 10) [NCBI Gene 6663], MITF (melanocyte inducing transcription factor) [NCBI Gene 4286], TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040], SOX6 (SRY-box transcription factor 6) [NCBI Gene 55553], MLANA (melan-A) [NCBI Gene 2315] - **Diseases:** melanoma (MONDO:0005105) ## Full-text entities - **Genes:** SOX6 (SRY-box transcription factor 6) [NCBI Gene 55553] {aka HSSOX6, SOXD, TOLCAS}, DLX4 (distal-less homeobox 4) [NCBI Gene 1748] {aka BP1, DLX7, DLX8, DLX9, OFC15}, SOX10 (SRY-box transcription factor 10) [NCBI Gene 6663] {aka DOM, PCWH, SOX-10, WS2E, WS4, WS4C}, Dlx4os (distal-less homeobox 4, opposite strand) [NCBI Gene 320453] {aka A730090H04Rik, Dlx4as}, Dlx4 (distal-less homeobox 4) [NCBI Gene 13394] {aka Dlx-4, Dlx7}, VCL (vinculin) [NCBI Gene 7414] {aka CMD1W, CMH15, HEL114, MV, MVCL, VINC}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], DICER1 (dicer 1, ribonuclease III) [NCBI Gene 23405] {aka DCR1, Dicer, Dicer1e, GLOW, HERNA, K12H4.8-LIKE}, NOD2 (nucleotide binding oligomerization domain containing 2) [NCBI Gene 64127] {aka ACUG, BLAU, BLAUS, CARD15, CD, CLR16.3}, LMNA (lamin A/C) [NCBI Gene 4000] {aka CDCD1, CDDC, CMD1A, CMT2B1, EMD2, FPL}, CTCF (CCCTC-binding factor) [NCBI Gene 10664] {aka CFAP108, FAP108, MRD21}, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 2597] {aka G3PD, GAPD, HEL-S-162eP}, Mlana (melan-A) [NCBI Gene 77836] {aka A930034P04Rik, Mart1}, TIMP1 (TIMP metallopeptidase inhibitor 1) [NCBI Gene 7076] {aka CLGI, EPA, EPO, HCI, TIMP, TIMP-1}, MLANA (melan-A) [NCBI Gene 2315] {aka MART-1, MART1}, RPL19 (ribosomal protein L19) [NCBI Gene 6143] {aka L19, eL19}, Lmna (lamin A) [NCBI Gene 16905] {aka Dhe}, Sox10 (SRY (sex determining region Y)-box 10) [NCBI Gene 20665] {aka Dom, Sox21, gt}, Snai1 (snail family zinc finger 1) [NCBI Gene 20613] {aka Sna, Sna1, Snail, Snail1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, Vcl (vinculin) [NCBI Gene 22330] {aka 9430097D22}, Sox6 (SRY (sex determining region Y)-box 6) [NCBI Gene 20679] {aka SOX-LZ}, Sox2 (SRY (sex determining region Y)-box 2) [NCBI Gene 20674] {aka Sox-2, lcc, ysb}, Actb (actin, beta) [NCBI Gene 11461] {aka Actx, E430023M04Rik, beta-actin}, MITF (melanocyte inducing transcription factor) [NCBI Gene 4286] {aka CMM8, COMMAD, MI, MITF-A, WS2, WS2A}, Mitf (melanogenesis associated transcription factor) [NCBI Gene 17342] {aka BCC2, Bhlhe32, Gsfbcc2, Vitiligo, Wh, bw}, H19 (H19 imprinted maternally expressed transcript) [NCBI Gene 283120] {aka ASM, ASM1, BWS, D11S813E, GMRSP, LINC00008}, TGFB3 (transforming growth factor beta 3) [NCBI Gene 7043] {aka ARVD, ARVD1, LDS5, RNHF, TGF-beta3} - **Diseases:** Cutaneous melanoma (MESH:C562393), Cancer (MESH:D009369), LMC (MESH:D008545), Metastasis (MESH:D009362), melan-a melanocytes (MESH:D009508), skin cancer (MESH:D012878) - **Chemicals:** MTT (MESH:C070243), NaCl (MESH:D012965), HCl (MESH:D006851), CO2 (MESH:D002245), sodium tetraborate (MESH:C010634), NO (MESH:D009614), Penicillin (MESH:D010406), TBS (MESH:D013725), PBS (MESH:D007854), borax (MESH:C018851), formaldehyde (MESH:D005557), insulin (MESH:D007328), TRIzol (MESH:C411644), geneticin (MESH:C010680), CaCl2 (MESH:D002122), PMA (MESH:D013755), paraformaldehyde (MESH:C003043), SDS (MESH:D012967), NP-40 (MESH:C010615), SYBR Green (MESH:C098022), Lipofectamine (MESH:C086724), Toluidine blue (MESH:D014048), PVDF (MESH:C024865), mitomycin C. (MESH:D016685), Streptomycin (MESH:D013307), agarose (MESH:D012685), 4C11 (-), poly(A) (MESH:D011061) - **Species:** Cricetulus griseus (Chinese hamster, species) [taxon 10029], Rattus norvegicus (brown rat, species) [taxon 10116], Heterocephalus glaber (naked mole rat, species) [taxon 10181], Nannospalax galili (Upper Galilee mountains blind mole rat, species) [taxon 1026970], Mus pahari (Gairdner's shrew-mouse, species) [taxon 10093], Homo sapiens (human, species) [taxon 9606], Mus spicilegus (mound-building mouse, species) [taxon 10103], Chinchilla lanigera (long-tailed chinchilla, species) [taxon 34839], Mus caroli (ricefield mouse, species) [taxon 10089], Mus spretus (Algerian mouse, species) [taxon 10096], Mus musculus (house mouse, species) [taxon 10090], Felis catus (cat, species) [taxon 9685] - **Cell lines:** 4C — Mus musculus (Mouse), Hybridoma (CVCL_J640), WM983C — Homo sapiens (Human), Melanoma, Cancer cell line (CVCL_A338), 4C11-melanoma — Homo sapiens (Human), Melanoma, Cancer cell line (CVCL_W877), -2 — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_A628), Leibovitz's L-15 — Mus musculus (Mouse), Hybridoma (CVCL_U609), -3 — Mus musculus (Mouse), Hybridoma (CVCL_C6V6), WM35 — Homo sapiens (Human), Cutaneous melanoma, Cancer cell line (CVCL_0580), 4C11 — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_ZJ85), -1 — Mus musculus (Mouse), Hybridoma (CVCL_C7RB) ## Figures 14 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13003849/full.md --- Source: https://tomesphere.com/paper/PMC13003849