# Role of CPT1A as a lysine succinyltransferase in tumorigenesis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $363,713

## Abstract

Project Summary
Oncogenic or tumor suppressive signaling often causes imbalances in posttranslational modifications (PTMs)
in human cancer. The receptor tyrosine kinase HER2 is an oncogene amplified or overexpressed in
approximately 25% of breast cancers and is associated with tumor aggressiveness and poor prognosis. A
recent study demonstrated that HER2 is translocated to mitochondria in a kinase activity-dependent manner to
alter metabolism and promote drug resistance in breast cancer cells. Consistent with these findings, our recent
study showed that oncogenic fibroblast growth factor receptor (FGFR) 1, which is also localized in
mitochondria, directly tyrosine phosphorylates mitochondrial pyruvate dehydrogenase kinase (PDHK) 1,
enhancing its enzyme activity to promote tumor growth in mice. Taken together, these results strongly suggest
that mitochondrial localization of oncogenic tyrosine kinases, including HER2, regulate mitochondrial metabolic
pathways that contribute to tumor growth. However, which mitochondrial metabolic enzymes are regulated by
HER2 in breast cancer is totally unknown. Thus, we performed phospho-proteomic analyses of mitochondria-
enriched fractions from HER2+ BT474 breast cancer cells and found that mitochondrial carnitine
palmitoyltransferase (CPT) 1A is tyrosine phosphorylated at Y514. Further biochemical analyses showed that
CPT1A Y514 phosphorylation by HER2 promotes its carnitine palmitoyltransferase (CPTase) activity.
Interestingly, we recently found that CPT1A has an additional enzymatic activity as a lysine succinyltransferase
(LSTase) to succinylate lysine residues of substrate proteins in vitro and in vivo .To our knowledge, CPT1A is a
first and only LSTase in mammalian cells. Importantly, mutation of CPT1A Gly710 (G710E) selectively
inactivated CPTase activity but not LSTase activity. Similar to CPT1A WT, CPT1A G710E increased total
lysine succinylation in cells without affecting intracellular succinyl-CoA levels. These findings suggest the
unprecedented role of CPT1A as LSTase that can regulate lysine succinylation-dependent signal transduction
in cells independent of its canonical CPTase activity that facilitates mitochondrial fatty acid oxidation (FAO)
pathway. Notably, however, how the LSTase activity of CPT1A is regulated and whether LSTase activity is
important for tumorigenesis is not known. Previous studies reported that multiple types of cancers including
melanoma, prostate, breast, and ovarian cancers showed elevated expression of CPT1A and knockdown of
CPT1A with si/shRNAs decreased cancer cell proliferation. We also found that high CPT1A mRNA expression
in HER2+ breast cancer patients strongly correlates with reduced survival while no correlation between CPT1A
mRNA expression and reduced patient survival was observed in other types of breast tumors. In addition, we
found that knockdown of CPT1A, as well as inhibition of HER2 by lapatinib, decreased CPT1A-subsrate motif
LVxxK succinylation and supp...

## Key facts

- **NIH application ID:** 9878076
- **Project number:** 5R01CA225680-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Taro Hitosugi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,713
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878076

## Citation

> US National Institutes of Health, RePORTER application 9878076, Role of CPT1A as a lysine succinyltransferase in tumorigenesis (5R01CA225680-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878076. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*