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<p>CLPTM1L has been identified as a susceptibility gene associated with nasopharyngeal carcinoma (NPC) risk, but its biological function and underlying mechanisms remain unclear. Here, we demonstrate that CLPTM1L is highly expressed in NPC patients and is associated with poor prognosis. Functional assays reveal that CLPTM1L overexpression significantly enhances NPC cell proliferation, migration and invasion, whereas its knockdown induces apoptosis and suppresses tumor growth. We further uncover that the transcription factor KLF1 directly binds to the promoter of CLPTM1L, driving its transcriptional activation. Transcriptome analysis indicates that CLPTM1L regulates various lipid metabolic pathways, notably upregulating SREBP1, a key metabolic regulator, thereby increasing intracellular free fatty acid levels in NPC cells. Mechanically, CLPTM1L interacts with the lipid raft-associated protein ERLIN2 to cooperatively stabilize SREBP1 protein levels by inhibiting its ubiquitination. Furthermore, knockdown of either ERLIN2 or SREBP1 remarkably inhibits the proliferation and migration capabilities of NPC cells, synergizing with CLPTM1L depletion. Importantly, SREBP1 overexpression markedly restored the inhibitory effects mediated by CLPTM1L and ERLIN2 knockdown, underscoring SREBP1 as a critical mediator in CLPTM1L’s oncogenic role. These findings delineate a novel pathogenic mechanism in NPC, highlighting the KLF1/CLPTM1L/ERLIN2/SREBP1 regulatory cascade as a promising therapeutic target for NPC treatment.</p>

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CLPTM1L interacts with ERLIN2 to stabilize SREBP1 and drive tumorigenesis in nasopharyngeal carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月23日

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  • Jian Zhang,
  • Shu-Qiang Liu,
  • Xiang-Yu Xiong,
  • Ya-Qing Zhou,
  • Pan-Pan Wei,
  • Xin-Yuan Guan,
  • Jin-Xin Bei,
  • Qian Cui,
  • Chun-Ling Luo

摘要

CLPTM1L has been identified as a susceptibility gene associated with nasopharyngeal carcinoma (NPC) risk, but its biological function and underlying mechanisms remain unclear. Here, we demonstrate that CLPTM1L is highly expressed in NPC patients and is associated with poor prognosis. Functional assays reveal that CLPTM1L overexpression significantly enhances NPC cell proliferation, migration and invasion, whereas its knockdown induces apoptosis and suppresses tumor growth. We further uncover that the transcription factor KLF1 directly binds to the promoter of CLPTM1L, driving its transcriptional activation. Transcriptome analysis indicates that CLPTM1L regulates various lipid metabolic pathways, notably upregulating SREBP1, a key metabolic regulator, thereby increasing intracellular free fatty acid levels in NPC cells. Mechanically, CLPTM1L interacts with the lipid raft-associated protein ERLIN2 to cooperatively stabilize SREBP1 protein levels by inhibiting its ubiquitination. Furthermore, knockdown of either ERLIN2 or SREBP1 remarkably inhibits the proliferation and migration capabilities of NPC cells, synergizing with CLPTM1L depletion. Importantly, SREBP1 overexpression markedly restored the inhibitory effects mediated by CLPTM1L and ERLIN2 knockdown, underscoring SREBP1 as a critical mediator in CLPTM1L’s oncogenic role. These findings delineate a novel pathogenic mechanism in NPC, highlighting the KLF1/CLPTM1L/ERLIN2/SREBP1 regulatory cascade as a promising therapeutic target for NPC treatment.