HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis
Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou
Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou
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Research Article Cell biology Oncology

HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis

Abstract

KRAS mutations serve as key oncogenic drivers in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Despite the advancement of KRAS inhibitors, such as MRTX1133, for PDAC treatment, intrinsic and acquired resistance remain major barriers to their clinical efficacy. This study underscored the role of histone deacetylase 5 (HDAC5) loss in mediating intrinsic resistance to KRASG12D inhibitors. Mechanistically, HDAC5 promoted c-Myc degradation by deacetylating K148, thereby facilitating NEDD4-mediated ubiquitination at this site. The loss of HDAC5 resulted in hyperacetylation of c-Myc at K148, impeding the ubiquitination and subsequent degradation process of c-Myc following deacetylation. Consequently, c-Myc stability and transcriptional activity were sustained even under KRAS/MEK/ERK pathway inhibition, reinforcing MAPK signaling and promoting cell survival despite KRAS suppression. Our data further demonstrated that pharmacological or genetic inhibition of c-Myc effectively reversed the resistance phenotype mediated by HDAC5 loss, suggesting a therapeutic strategy centered on KRAS-MYC dual-node blockade. Furthermore, the expression levels of HDAC5 and the acetylation status of c-Myc may serve as biomarkers for predicting the therapeutic response to MRTX1133. These findings provide insights into overcoming resistance to KRASG12D inhibitors and offer potential biomarkers and combinatorial therapeutic strategies for precision treatment of PDAC.

Authors

Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou

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Figure 4

Loss of HDAC5 promotes the stabilization of c-Myc protein.

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Loss of HDAC5 promotes the stabilization of c-Myc protein. (A and B) Wes...
(A and B) Western blot (A) and RT-qPCR (B) analyses of c-Myc expression in PANC-1 and AsPC-1 cells infected with indicated shRNAs for 48 hours (n = 3). (C) Western blot analysis of c-Myc protein levels in PANC-1 and AsPC-1 cells transfected with indicated plasmids and treated with DMSO or MG132 (10 μM, 8 hours). EV, empty vector. (D) RT-qPCR analysis of c-Myc mRNA in PANC-1 and AsPC-1 cells transfected with indicated plasmids for 48 hours (n = 3). (E) Immunofluorescence analysis of c-Myc in PANC-1 cells transfected with indicated plasmids for 48 hours. Representative images and fluorescence intensity quantification are shown (n = 5). (F) Western blot analysis and quantification of c-Myc protein stability in control or HDAC5-knockdown PANC-1 and AsPC-1 cells treated with cycloheximide (CHX, 50 μg/mL) for indicated times (n = 3). (G) Colocalization analysis of the merged images in E, showing pixel intensity profiles along the white line from left to right in each panel. Colors correspond to the merged images: green for c-Myc and blue for DAPI. All data are presented as the mean ± SD. Statistical significance was determined by 1-way ANOVA followed by Dunnett’s multiple comparisons test (B, D, and E) or 2-way ANOVA followed by Tukey multiple comparisons test (F). **P < 0.01, ***P < 0.001.