The human HEAT repeat-containing protein 1 (HEATR1), consisting of 2144 amino acids, is a member of the UTP10 family and contains one HEAT repeat at its C-terminal. HEATR1 has been reported to regulate cytotoxic T lymphocytes and rRNA synthesis, while its functions in tumors are poorly understood. Here, we found that HEATR1 competed with Keap1 for binding to p62/sequestosome 1 (SQSTM1), resulted in up-regulation of Keap1, which then inhibited Nrf2 signaling in pancreatic cancer cells. HEATR1 knockdown enhanced proliferation and gemcitabine resistance of pancreatic cancer cells. Moreover, HEATR1 deficiency significantly improved xenografts growth and led to gemcitabine resistance in pancreatic cancer cell-derived xenografts through up-regulating Nrf2 signaling. By analyzing tumor tissue samples from pancreatic cancer patients, we found that low expression of HEATR1 was closely correlated with poor prognosis and clinicopathological features. Collectively, we suggest that HEATR1 deficiency promotes proliferation and gemcitabine resistance of pancreatic cancer through up-regulating Nrf2 signaling, indicating that HEATR1 may be a promising therapeutic target for pancreatic cancer.

人类含有 HEAT 重复序列的蛋白质 1 (HEATR1) 由 2144 个氨基酸组成，是 UTP10 家族的成员，在其 C 端包含一个 HEAT 重复序列。据报道，HEATR1 可调节细胞毒性 T 淋巴细胞和 rRNA 合成，而对其在肿瘤中的功能知之甚少。在这里，我们发现 HEATR1 与 Keap1 竞争结合 p62/sequestosome 1 (SQSTM1)，导致 Keap1 上调，然后抑制胰腺癌细胞中的 Nrf2 信号传导。HEATR1 敲低增强了胰腺癌细胞的增殖和吉西他滨耐药性。此外，HEATR1 缺乏显着改善了异种移植物的生长，并通过上调 Nrf2 信号传导导致胰腺癌细胞衍生的异种移植物对吉西他滨产生耐药性。通过分析胰腺癌患者的肿瘤组织样本，我们发现HEATR1的低表达与预后不良和临床病理学特征密切相关。总的来说，我们认为 HEATR1 缺乏通过上调 Nrf2 信号传导促进胰腺癌的增殖和吉西他滨耐药性，表明 HEATR1 可能是胰腺癌的有希望的治疗靶点。