TIPE regulates glucometabolic reprogramming by modulating LDHA expression in triple-negative breast cancer

doi:10.19401/j.cnki.1007-3639.2025.04.006

Abstract

Abstract:

Background and purpose: Tumor necrosis factor alpha-induced protein 8 (TNFAIP8), also called TIPE, plays critical regulatory roles in various malignancies, yet its molecular mechanisms in metabolic reprogramming of triple-negative breast cancer (TNBC) remain elusive. This study aimed to elucidate how TIPE regulates the expression of the glycolytic key enzyme lactate dehydrogenase A to influence TNBC cell proliferation and glycolytic reprogramming, thereby providing potential molecular targets for TNBC therapy. Methods: Stable TIPE-knockdown MDA-MB-231 cell lines were established using a lentiviral shRNA system and selected with puromycin. Transcriptome sequencing was used to analyze TIPE's impact on TNBC glycolytic pathways. Extracellular acidification rate (ECAR) was measured using the Seahorse XF Analyzer, complemented by lactate production assays to evaluate glycolytic capacity. Co-IP/MS was carried out to identify TIPE-interacting proteins, with subsequent validation of TIPE-LDHA interaction through co-transfection of TIPE-Myc and LDHA-Flag plasmids in HEK-293T cells. Protein stability was assessed via cycloheximide (CHX) chase and ubiquitination assays. The cell counting kit-8 (CCK-8) assay and animal experiments (Approval Number for Animal Ethics: 202212007) were conducted to investigate how TIPE affects the proliferation and glucometabolic reprogramming of TNBC by mediating LDHA. Results: TIPE promoted glycolytic metabolic reprogramming in TNBC. Knockdown of TIPE significantly inhibited TNBC glycolytic activity and glycolytic capacity (P<0.001). TIPE interacted with the key glycolytic enzyme LDHA and suppressed its degradation rate through a ubiquitination-dependent mechanism. Cellular experiments demonstrated that TIPE mediated LDHA to enhance TNBC cell proliferation (P<0.001) and glycolytic activity (P<0.001). Animal studies confirmed that TIPE knockdown significantly suppressed tumor volume (P<0.05) and weight (P<0.01), with a positive correlation between TIPE and LDHA expression levels in tumor tissues. Conclusion: TIPE enhances TNBC cell proliferation and glycolytic capacity by inhibiting LDHA ubiquitination-mediated degradation.

Key words: TIPE, Triple-negative breast cancer, Glycometabolic reprogramming, Lactate dehydrogenase A, Ubiquitination

HU Wei, REN Xiaomeng, WANG Yang, ZHAO Peiqing, CAO Kai. TIPE regulates glucometabolic reprogramming by modulating LDHA expression in triple-negative breast cancer[J]. China Oncology, 2025, 35(4): 386-393.

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References 16

[1]	YANG M H, ZHANG Y Z, LIU G P, et al. TIPE1 inhibits osteosarcoma tumorigenesis and progression by regulating PRMT1 mediated STAT3 arginine methylation[J]. Cell Death Dis, 2022, 13(9): 815. doi: 10.1038/s41419-022-05273-y pmid: 36151091
[2]	HU W, FENG C M, LIU L Y, et al. TIPE1 inhibits breast cancer proliferation by downregulating ERK phosphorylation and predicts a favorable prognosis[J]. Front Oncol, 2019, 9: 400. doi: 10.3389/fonc.2019.00400 pmid: 31179241
[3]	LOU Y W, TIAN X Q, SUN C, et al. TNFAIP8 protein functions as a tumor suppressor in inflammation-associated colorectal tumorigenesis[J]. Cell Death Dis, 2022, 13(4): 311. doi: 10.1038/s41419-022-04769-x pmid: 35387985
[4]	TIAN M J, YANG L, ZHAO Z Q, et al. TIPE drives a cancer stem-like phenotype by promoting glycolysis via PKM2/HIF-1α axis in melanoma[J]. eLife, 2024, 13: RP92741.
[5]	HAN B, ZHENG R, ZENG H, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4(1): 47-53.
[6]	MA L F, XU L L, YUAN L J, et al. Discovery of NO donor-aurovertin hybrids as dual ferroptosis and apoptosis inducers for treating triple-negative breast cancer[J]. J Med Chem, 2024, 67(15): 13089-13105.
[7]	SUN X H, VERMA S P, JIA G C, et al. Case-case genome-wide analyses identify subtype-informative variants that confer risk for breast cancer[J]. Cancer Res, 2024, 84(15): 2533-2548. doi: 10.1158/0008-5472.CAN-23-3854 pmid: 38832928
[8]	YANG F, XIAO Y, DING J H, et al. Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy[J]. Cell Metab, 2023, 35(1): 84-100.e8.
[9]	FENDT S M. 100 years of the Warburg effect: a cancer metabolism endeavor[J]. Cell, 2024, 187(15): 3824-3828.
[10]	DU Y, WEI N, MA R L, et al. A miR-210-3p regulon that controls the Warburg effect by modulating HIF-1α and p53 activity in triple-negative breast cancer[J]. Cell Death Dis, 2020, 11(9): 731. doi: 10.1038/s41419-020-02952-6 pmid: 32908121
[11]	YU Y H, DENG H F, WANG W W, et al. LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m6 A modification in triple-negative breast cancer[J]. Clin Transl Med, 2024, 14(2): e1583.
[12]	HE L, LV S N, MA X J, et al. ErbB2 promotes breast cancer metastatic potential via HSF1/LDHA axis-mediated glycolysis[J]. Med Oncol, 2022, 39(4): 45.
[13]	CUI J J, SHI M, XIE D C, et al. FOXM1 promotes the Warburg effect and pancreatic cancer progression via transactivation of LDHA expression[J]. Clin Cancer Res, 2014, 20(10): 2595-2606.
[14]	DAI H J, XU W T, WANG L L, et al. Loss of SPRY2 contributes to cancer-associated fibroblasts activation and promotes breast cancer development[J]. Breast Cancer Res, 2023, 25(1): 90. doi: 10.1186/s13058-023-01683-8 pmid: 37507768
[15]	AN Y J, JO S, KIM J M, et al. Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism[J]. Exp Mol Med, 2023, 55(10): 2238-2247.
[16]	LIU S G, XIANG Y N, WANG B S, et al. USP1 promotes the aerobic glycolysis and progression of T-cell acute lymphoblastic leukemia via PLK1/LDHA axis[J]. Blood Adv, 2023, 7(13): 3099-3112.