Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Breast Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
PeerJ. 2024 Jul 12;12:e17749. doi: 10.7717/peerj.17749. eCollection 2024.
Triple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.
三阴性乳腺癌（TNBC）作为乳腺癌最具侵袭性的分子亚型，其特征是癌细胞增殖活跃，患者预后不良。异常的脂质代谢有助于癌症的恶性进程。研究观察到 TNBC 中胆固醇生物合成显著增强。然而，TNBC 中胆固醇生物合成异常增加的机制尚不清楚。因此，我们鉴定出丝氨酸/苏氨酸蛋白激酶家族成员 PKMYT1 是 TNBC 细胞中胆固醇合成的关键驱动因子。在 TNBC 中异常高表达的 PKMYT1 预示着预后不良。此外，PKMYT1 通过激活 TNF/TNF 受体相关因子 1（TRAF1）/AKT 通路，促进固醇调节元件结合蛋白 2（SREBP2）介导的与胆固醇生物合成相关酶的表达。值得注意的是，下调 PKMYT1 可显著抑制他汀类药物介导的胆固醇生物合成的反馈上调，而敲低 PKMYT1 可促进 TNBC 细胞中阿托伐他汀的药物敏感性。总之，本研究揭示了 PKMYT1 在 TNBC 胆固醇生物合成中的新功能，为靶向肿瘤代谢重编程提供了新的靶点。
