Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3.

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-02-25 Epub Date: 2025-01-31 DOI:10.1016/j.celrep.2025.115250

Ling Ye, Shengqi Shen, Qiankun Mao, Hui Lu, Haiying Liu, Pinggen Zhang, Zetan Jiang, Wenhao Ma, Yuchen Sun, Yiyang Chu, Zilong Zhou, Rui Liu, Jian Li, Shi-Ting Li, Ping Gao, Huafeng Zhang

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Abstract

Metabolic enzymes play significant roles in the pathogenesis of various cancers through both canonical and noncanonical functions. Hexokinase domain-containing protein 1 (HKDC1) functions beyond glucose metabolism, but its underlying mechanisms in tumorigenesis are not fully understood. Here, we demonstrate that nuclear-localized HKDC1 acts as a protein kinase to promote hepatocellular carcinoma (HCC) cell proliferation. Mechanistically, HKDC1 phosphorylates RB binding protein 5 (RBBP5) at Ser497, which is crucial for MLL1 complex assembly and subsequent histone H3 lysine 4 trimethylation (H3K4me3) modification. This leads to the transcriptional activation of mitosis-related genes, thereby driving cell cycle progression and proliferation. Notably, targeting HKDC1's protein kinase activity, but not its HK activity, blocks RBBP5 phosphorylation and suppresses tumor growth. Clinical analysis further reveals that RBBP5 phosphorylation positively correlates with HKDC1 levels and poor HCC prognosis. These findings highlight the protein kinase function of HKDC1 in the activation of H3K4me3, gene expression, and HCC progression.

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代谢酶通过典型和非典型功能在各种癌症的发病机制中发挥着重要作用。含六磷酸酶结构域的蛋白 1（HKDC1）的功能超越了葡萄糖代谢，但其在肿瘤发生中的潜在机制尚未完全清楚。在这里，我们证明了核定位的 HKDC1 可作为蛋白激酶促进肝细胞癌（HCC）细胞增殖。从机制上讲，HKDC1 可使 RB 结合蛋白 5（RBBP5）在 Ser497 处磷酸化，而 Ser497 对 MLL1 复合物的组装和随后的组蛋白 H3 赖氨酸 4 三甲基化（H3K4me3）修饰至关重要。这将导致有丝分裂相关基因的转录激活，从而推动细胞周期的进展和增殖。值得注意的是，靶向 HKDC1 的蛋白激酶活性（而非其 HK 活性）可阻断 RBBP5 磷酸化并抑制肿瘤生长。临床分析进一步显示，RBBP5磷酸化与HKDC1水平和HCC不良预后呈正相关。这些发现突显了 HKDC1 在激活 H3K4me3、基因表达和 HCC 进展中的蛋白激酶功能。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.