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CDK4/6 inhibitors downregulate the ubiquitin-conjugating enzymes UBE2C/S/T involved in the ubiquitin–proteasome pathway in ER + breast cancer

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A Correction to this article was published on 10 September 2022

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Abstract

Purpose

Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin–proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins.

Methods

We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts.

Results

We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C.

Conclusions

Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.

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Acknowledgements

This study was partially funded by the grants to JIL: MOST 110-2314-B-A49A-549 (Ministry of Science and Technology), MLCF-V111_A11102 (Melissa Lee Cancer Foundation), Taiwan Clinical Oncology Research Foundation, and 109DHA0100490 (Taipei Veterans General Hospital internal grant).

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Authors and Affiliations

  1. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chih-Yi Lin, Chung-Jen Yu & Jiun-I. Lai

  2. School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chun-Yu Liu, Ta-Chung Chao & Ling-Ming Tseng

  3. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Yu Liu, Ta-Chung Chao & Jiun-I. Lai

  4. Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Yu Liu

  5. Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Yu Liu, Ta-Chung Chao, Chi-Cheng Huang, Ling-Ming Tseng & Jiun-I. Lai

  6. Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

    Chi-Cheng Huang & Ling-Ming Tseng

  7. Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

    Jiun-I. Lai

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Lin, CY., Yu, CJ., Liu, CY. et al. CDK4/6 inhibitors downregulate the ubiquitin-conjugating enzymes UBE2C/S/T involved in the ubiquitin–proteasome pathway in ER + breast cancer. Clin Transl Oncol 24, 2120–2135 (2022). https://doi.org/10.1007/s12094-022-02881-0

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