# The MYBL2-GTSE1 axis promotes laryngeal squamous cell carcinoma progression by regulating PI3K/AKT-dependent glycolytic reprogramming **Authors:** Yiyin Liang, Cansi Wang, Tianjiao Ren, Bo Zhang, Yaqi Liu, Rong Fu, Juan Feng PMC · DOI: 10.1080/15384047.2026.2648193 · Cancer Biology & Therapy · 2026-03-22 ## TL;DR This study shows how the MYBL2-GTSE1 pathway drives laryngeal cancer growth by altering cell metabolism, suggesting a new target for treatment. ## Contribution Identifies a novel MYBL2-GTSE1-PI3K/AKT axis driving glycolytic reprogramming in laryngeal squamous cell carcinoma. ## Key findings - MYBL2 overexpression correlates with poor prognosis in LSCC and activates GTSE1 transcription. - MYBL2-GTSE1 signaling enhances glycolysis and suppresses mitochondrial respiration via PI3K/AKT pathway. - Inhibiting GTSE1 or PI3K reverses MYBL2-driven tumor growth in vitro and in vivo. ## Abstract Laryngeal squamous cell carcinoma (LSCC) is a common head and neck malignancy with poor prognosis. The role of MYBL2, an oncogenic transcription factor, in the glycolytic reprogramming of LSCC remains unclear. We integrated RNA-sequencing with public databases (TCGA, GEO) and tissue microarrays to assess MYBL2 expression and its clinical significance. Transcriptional regulation was verified by ChIP-qPCR and luciferase reporter assays. Signaling pathways and metabolic profiles were examined using Western blotting and Seahorse analysis (ECAR/OCR). Biological functions were evaluated by in vitro functional assays and in vivo xenograft models in female BALB/c nude mice. MYBL2 was significantly overexpressed in LSCC tissues and correlated with poor prognosis. Mechanistically, MYBL2 directly activates GTSE1 transcription. This regulation stimulates PI3K/AKT signaling to upregulate key glycolytic proteins (PKM2, HK2, GLUT1, LDHA), thereby driving metabolic reprogramming characterized by elevated glycolysis (ECAR) and suppressed mitochondrial respiration (OCR). Functionally, MYBL2 overexpression enhanced the proliferation, migration, and invasion of LSCC cells in vitro and promoted tumor growth in vivo. Importantly, these oncogenic effects were effectively reversed by GTSE1 knockdown or PI3K inhibition with LY294002, validating the pathway's functional significance. The MYBL2-GTSE1 axis promotes LSCC progression through PI3K/AKT-mediated metabolic reprogramming, representing a promising therapeutic target. Schematic illustration of the MYBL2/GTSE1/PI3K-AKT axis promoting glycolytic reprogramming and LSCC progression. ## Linked entities - **Genes:** MYBL2 (MYB proto-oncogene like 2) [NCBI Gene 4605], GTSE1 (G2 and S-phase expressed 1) [NCBI Gene 51512], PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) [NCBI Gene 5290], AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207], PKM (pyruvate kinase M1/2) [NCBI Gene 5315], HK2 (hexokinase 2) [NCBI Gene 3099], SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513], LDHA (lactate dehydrogenase A) [NCBI Gene 3939] - **Chemicals:** LY294002 (PubChem CID 3973) - **Diseases:** laryngeal squamous cell carcinoma (MONDO:0005595) ## Full-text entities - **Genes:** PFKL (phosphofructokinase, liver type) [NCBI Gene 5211] {aka ATP-PFK, PFK-B, PFK-L}, GPI (glucose-6-phosphate isomerase) [NCBI Gene 2821] {aka AMF, CNSHA4, GNPI, NLK, PGI, PHI}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, AKT2 (AKT serine/threonine kinase 2) [NCBI Gene 208] {aka HIHGHH, PKBB, PKBBETA, PRKBB, RAC-BETA}, APC (APC regulator of Wnt signaling pathway) [NCBI Gene 324] {aka BTPS2, DESMD, DP2, DP2.5, DP3, GS}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, MYB (MYB proto-oncogene, transcription factor) [NCBI Gene 4602] {aka Cmyb, c-myb, c-myb_CDS, efg}, Hk2 (hexokinase 2) [NCBI Gene 15277] {aka HKII}, PKM (pyruvate kinase M1/2) [NCBI Gene 5315] {aka CTHBP, HEL-S-30, OIP3, PK3, PKM2, TCB}, MYBL2 (MYB proto-oncogene like 2) [NCBI Gene 4605] {aka B-MYB, BMYB}, TENM1 (teneurin transmembrane protein 1) [NCBI Gene 10178] {aka ODZ1, ODZ3, TEN-M1, TEN1, TNM, TNM1}, MALAT1 (metastasis associated lung adenocarcinoma transcript 1) [NCBI Gene 378938] {aka HCN, LINC00047, NCRNA00047, NEAT2, PRO2853, miPEP-52}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, HK2 (hexokinase 2) [NCBI Gene 3099] {aka HKII, HXK2}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, Slc2a1 (solute carrier family 2 (facilitated glucose transporter), member 1) [NCBI Gene 20525] {aka GT1, Glut-1, Glut1, M100200, Rgsc200}, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 2597] {aka G3PD, GAPD, HEL-S-162eP}, Ldha (lactate dehydrogenase A) [NCBI Gene 16828] {aka Ldh1, Ldhm, l7R2}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, NRAS (NRAS proto-oncogene, GTPase) [NCBI Gene 4893] {aka ALPS4, CMNS, N-ras, NCMS, NRAS1, NS6}, Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}, CMPK1 (cytidine/uridine monophosphate kinase 1) [NCBI Gene 51727] {aka CK, CMK, CMPK, UMK, UMP-CMPK, UMPK}, MCL1 (MCL1 apoptosis regulator, BCL2 family member) [NCBI Gene 4170] {aka BCL2L3, EAT, MCL1-ES, MCL1L, MCL1S, Mcl-1}, ANXA5 (annexin A5) [NCBI Gene 308] {aka ANX5, CPB-I, ENX2, HEL-S-7, PP4, RPRGL3}, LDHA (lactate dehydrogenase A) [NCBI Gene 3939] {aka GSD11, HEL-S-133P, LDHM, PIG19}, GTSE1 (G2 and S-phase expressed 1) [NCBI Gene 51512] {aka B99}, CDK2 (cyclin dependent kinase 2) [NCBI Gene 1017] {aka CDKN2, p33(CDK2)}, HK1 (hexokinase 1) [NCBI Gene 3098] {aka CNSHA5, HK, HK1-ta, HK1-tb, HK1-tc, HKD}, CCNE1 (cyclin E1) [NCBI Gene 898] {aka CCNE, pCCNE1}, Mybl2 (Myb proto-oncogene like 2) [NCBI Gene 17865] {aka B-Myb, Bmyb}, CDCA3 (cell division cycle associated 3) [NCBI Gene 83461] {aka GRCC8, TOME-1, TOME1}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, CCND2 (cyclin D2) [NCBI Gene 894] {aka KIAK0002, MPPH3}, HRAS (HRas proto-oncogene, GTPase) [NCBI Gene 3265] {aka C-BAS/HAS, C-H-RAS, C-HA-RAS1, CTLO, H-RASIDX, HAMSV}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, ENO1 (enolase 1) [NCBI Gene 2023] {aka ENO1-IT1, ENO1L1, HEL-S-17, MPB1, NNE, PPH}, ABRACL (ABRA C-terminal like) [NCBI Gene 58527] {aka C6orf115, Costars, HSPC280, PRO2013}, SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513] {aka CSE, DYT17, DYT18, DYT9, EIG12, GLUT}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, SLC16A14 (solute carrier family 16 member 14) [NCBI Gene 151473] {aka MCT14}, Gtse1 (G two S phase expressed protein 1) [NCBI Gene 29870] {aka B99, Gtse-1}, OPA3 (outer mitochondrial membrane lipid metabolism regulator OPA3) [NCBI Gene 80207] {aka MGA3}, POTEF (POTE ankyrin domain family member F) [NCBI Gene 728378] {aka A26C1B, POTE2alpha, POTEACTIN} - **Diseases:** lymph node metastasis (MESH:D008207), breast cancer (MESH:D001943), respiratory system tumor (MESH:D012142), Head and Neck Squamous Cell Carcinoma (MESH:D000077195), squamous cell carcinoma (MESH:D002294), NES (MESH:C537354), AMC-HN-8 (MESH:C563086), dislocation (MESH:D004204), HPLMEC (MESH:D009375), Tumor (MESH:D009369), gastric cancer (MESH:D013274), bladder cancer (MESH:D001749), hepatocellular carcinoma (MESH:D006528), Laryngeal cancer (MESH:D007822), T (MESH:D001260), head and neck cancer (MESH:D006258), NPC (MESH:D000077274), death (MESH:D003643), lung cancer (MESH:D008175), Disease (MESH:D004194), metastasis (MESH:D009362) - **Chemicals:** LY294002 (MESH:C085911), ATP (MESH:D000255), Hematoxylin (MESH:D006416), BAY-876 (MESH:C000620175), glucose (MESH:D005947), puromycin (MESH:D011691), water (MESH:D014867), AZD3965 (MESH:C000592351), antimycin A (MESH:D000968), glycine (MESH:D005998), FCCP (MESH:D002259), formaldehyde (MESH:D005557), PBS (MESH:D007854), PI (MESH:D010716), oligomycin A (MESH:C031004), DMSO (MESH:D004121), H&E (MESH:D006371), eosin (MESH:D004801), SDS (MESH:D012967), paraformaldehyde (MESH:C003043), rotenone (MESH:D012402), MK-2206 (MESH:C548887), TRIzol (MESH:C411644), BD356234 (-), agarose (MESH:D012685), 2-DG (MESH:D003847), mitomycin C (MESH:D016685), PVDF (MESH:C024865), Staurosporine (MESH:D019311), fatty acid (MESH:D005227), lactate (MESH:D019344), pentobarbital sodium (MESH:D010424), Crystal Violet (MESH:D005840), Oxygen (MESH:D010100) - **Species:** Mycoplasma (genus) [taxon 2093], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090] - **Mutations:** A to F, C through F, P0018S, A in A, C for A, I to K - **Cell lines:** N 8 — Mus musculus (Mouse), Transformed cell line (CVCL_D463), BTCC-1192 — Homo sapiens (Human), Finite cell line (CVCL_4J30), TU138 — Homo sapiens (Human), Lung small cell carcinoma, Cancer cell line (CVCL_Z025), TCHu262 — Mus musculus (Mouse), Hybridoma (CVCL_J807), AMC-HN-8 — Homo sapiens (Human), Laryngeal squamous cell carcinoma, Cancer cell line (CVCL_5966), T U 138 — Homo sapiens (Human), Astrocytoma, Cancer cell line (CVCL_0020), TU212 — Homo sapiens (Human), Head and neck squamous cell carcinoma, Cancer cell line (CVCL_4915), U 1 3 8 — Homo sapiens (Human), Fibrosarcoma, Cancer cell line (CVCL_9469), -8 — Xenopus laevis (African clawed frog), Spontaneously immortalized cell line (CVCL_4564), ORC0873 — Mus musculus (Mouse), Hybridoma (CVCL_KR48), SNL-497 — Homo sapiens (Human), Finite cell line (CVCL_9W74), TU686 — Homo sapiens (Human), Oropharyngeal squamous cell carcinoma, Cancer cell line (CVCL_6985), L S C C — Canis lupus familiaris (Dog), Canine mastocytoma, Cancer cell line (CVCL_1R44), BALB/c — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0184), RPC-050 — Mus musculus (Mouse), Mouse multiple myeloma, Cancer cell line (CVCL_R784), pRL — Mus musculus (Mouse), Transformed cell line (CVCL_U368), H N 8 — Mus musculus (Mouse), Hybridoma (CVCL_XK40), CCK-8 — Homo sapiens (Human), T-cell prolymphocytic leukemia, Cancer cell line (CVCL_5443) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC13011630/full.md ## Figures 8 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13011630/full.md ## References 65 references — full list in the complete paper: https://tomesphere.com/paper/PMC13011630/full.md --- Source: https://tomesphere.com/paper/PMC13011630