河南大学菅永平团队近日取得一项新成果。经过不懈努力，他们的论文发现了吡洛酮胺在结直肠癌中通过靶向HDAC6促进BECN1转录并激活自噬。这一研究成果于2026年3月30日发表在国际顶尖学术期刊《遗传学报》上。

在目前的研究中，研究小组发现吡洛酮胺（PO），一种抗真菌药物，作为一种新的CRC细胞增殖抑制剂，同时激活自噬，促进CRC细胞死亡，对正常细胞的细胞毒性最小。抑制自噬完全消除了PO诱导的细胞死亡，证实自噬是细胞死亡的主要途径。转录组学分析显示，PO显著上调beclin-1（BECN1）的表达，BECN1是一种重要的自噬相关基因。

结构分析表明，PO含有肟基，结构类似于基于羟酸盐的HDAC抑制剂。课题组研究人员还发现，PO特异性靶向并抑制HDAC6，导致组蛋白H3在赖氨酸9 （H3K9ac）处乙酰化增加。ChIP-qPCR和双荧光素酶检测证实，H3K9ac的增加促进了BECN1启动子上转录因子的结合，增强了BECN1的转录。在体内，PO有效降低HDAC6的表达，提高BECN1水平，促进自噬，抑制肿瘤生长。综上所述，PO选择性抑制HDAC6，促进H3K9组蛋白乙酰化，上调BECN1表达，诱导CRC细胞自噬依赖性细胞死亡。这些发现使PO成为开发HDAC6靶向结直肠癌治疗的一个有希望的候选者。

据悉，结直肠癌（CRC）是癌症相关死亡率的主要疾病，通常在治疗选择有限的晚期才被诊断出来。组蛋白去乙酰化酶（HDAC）在结直肠癌中经常过表达，通过表观遗传调控促进肿瘤细胞增殖和存活。

附：英文原文

Title: Piroctone olamine promotes BECN1 transcription and activates autophagy by targeting HDAC6 in colorectal cancer

Author: Cui, Cui-yun, Li, Qiu-tong, Xiang, Xiong-yan, Fu, Ting-yu, Kong, Cun-quan, Yu, Lu, Ni, Wei-dong, Zhao, Zi-long, Liu, Huai, Zhao, Qing-chun, Ma, Cui-xia, Chen, Lin, Shi, Jing-li, Xie, Qi, Sun, Xiao-ya, Xu, Zhi-xiang, Yan, Bei-zhan, Jian, Yong-ping

Issue&Volume: 2026-03-30

Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, often diagnosed at advanced stages when treatment options are limited. Histone deacetylases (HDACs) are frequently overexpressed in CRC, promoting tumor cell proliferation and survival through epigenetic regulation. In the current study, we identified piroctone olamine (PO), an antifungal agent, as a novel inhibitor of CRC cell proliferation which simultaneously activates autophagy to promote CRC cell death with minimal cytotoxicity to normal cells. Inhibition of autophagy completely abolished PO-induced cell death, confirming that autophagy is the primary pathway for cell death. Transcriptomic analysis revealed that PO significantly upregulated the expression of beclin-1 (BECN1), an essential autophagy-related gene. Structural analysis indicated that PO contains an oxime group, structurally similar to hydroxamate-based HDAC inhibitors. We also found that PO specifically targeted and inhibited HDAC6, leading to increased acetylation of histone H3 at lysine 9 (H3K9ac). The increase in H3K9ac promoted the binding of transcription factors at the BECN1 promoter, enhancing BECN1 transcription, as confirmed by ChIP-qPCR and dual-luciferase assays. In vivo, PO effectively reduced HDAC6 expression, elevated BECN1 levels, promoted autophagy, suppressed tumor growth in a syngeneic mouse CRC model. In conclusion, PO selectively inhibits HDAC6, promotes histone acetylation at H3K9, upregulates BECN1 expression, and induces autophagy-dependent cell death in CRC cells. These findings position PO as a promising candidate for the development of HDAC6-targeted therapies in CRC.

DOI: 10.1038/s41401-026-01784-y

Source: https://www.nature.com/articles/s41401-026-01784-y