自噬对于通过溶酶体的降解作用去除、降解和回收受损的细胞器、蛋白质和脂质非常重要。除了其分解代谢功能外，自噬在癌症和病毒介导的肿瘤发生中也很重要，包括人乳头瘤病毒 (HPV) 阳性癌症。 HPV 感染是头颈癌 (HNC) 子集的主要危险因素，目前尚无针对性的治疗方法。在此，我们评估了 HPV 阳性 HNC 中的自噬功能。我们发现，与 HPV 阴性细胞相比，HPV 阳性 HNC 细胞的自噬过程存在转录和功能损伤，HPV 阴性细胞通过敲低细胞转化的驱动因素 HPV E6/E7 癌蛋白而重新激活。我们发现癌蛋白 c-MYC 在 HPV 阳性细胞系中稳定并被触发。由于 c-MYC 竞争，这导致 MiT/TFE 转录因子与其自噬靶标的结合减少。因此，c-MYC的敲除诱导HPV阳性HNC细胞中自噬和溶酶体基因的上调，以及蛋白质水平上自噬标记物的增加。此外，HPV癌蛋白E7上调磷酸酶抑制剂CIP2A的表达，从而解释了HPV HNC细胞中c-MYC的上调和稳定性。 HNC 患者肿瘤组织中 CIP2A mRNA 表达与自噬基因表达呈负相关，首次显示其在转录自噬背景中的意义。 CIP2A 和 c-MYC 敲低以及 c-MYC 的药理下调均导致对顺铂治疗的耐药性增加。我们的结果不仅展示了 HPV 癌蛋白操纵宿主机制的新方法，而且还为自噬在化疗耐药中的作用提供了更多见解，可能对 HPV 阳性 HNC 靶向治疗产生影响。© 2023。作者。

Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.© 2023. The Author(s).